Intermediates for the production of N-substituted anilines, inhibitors of phospholipases A2

ABSTRACT

Compounds of the formula    &lt;IMAGE&gt; I  wherein R1, R2, R3, R4, R5, R6, R7, R8, n, m, o, p, and q are as hereinafter set forth, and, when R2 is hydrogen, pharmaceutically acceptable salts thereof with bases, are described. The compounds of formula 1 are potent inhibitors of phospholipases A2 (PLA2&#39;s) and are therefore useful in the treatment of inflammatory diseases, such as psosiasis, inflammatory bowel disease, asthma, allergy, arthritis, dermatitis, gout, pulmonary disease, myocardial ischemia/reperfusion, and trauma induced inflammation, such as spinal cord injury.

This is a division of application Ser. No. 07/914,825 filed Jul. 15,1992, now U.S. Pat. No. 5,324,747.

BRIEF SUMMARY OF THE INVENTION

The invention relates to compounds of the formula ##STR2## wherein R₁ ishydrogen or --(CH₂)_(m) COOR₂ ;

R₂ is hydrogen, (R₆)₂ N(CH₂)₂ --, R₆ COOCH₂ -- or --CH₂ CON(CH₂ CH₂ OH)₂;

R₃ is hydrogen, nitro, hydroxy, amino, CH₃ (CH₂)_(n) S(O)0-2--, CH₃(CH₂)_(n) --, CH₃ (CH₂)_(n) O--, R₅ COO--, R₅ OOC--, R₅ HNCOO--, R₅NHCO--, R₅ CONH--, R₅ NHCONH--, [CH₃ (CH₂)_(n) ]₂ NCO--, CH₃ (CH₂)_(n)CHOHCH₂ O--, (2-quinolinyl)methoxy, oleyloxy, linoleyloxy, R₈ OOC(CH₂)₀O--, (R₆ O)₂ PO(CH₂)_(p) O--, (HO) (R₆ O)PO(CH₂)_(p) O--, R₆ [O(CH₂)₂]_(q) O--, R₇ (CH₂)_(p) O--, or --O(CH₂)_(p) --pyridinium⁺ (OH--);

R₄ is CH₃ (CH₂)_(n) --, CH₃ (CH₂)_(n) O--, CF₃ SO₂ NH--, R₅ COO--, R₅OOC--, R₅ HNCOO--, R₅ NHCO--, R₅ NHCONH--, [CH₃ (CH₂)_(n) ]₂ NCO--, CH₃(CH₂)_(n) CHOHCH₂ O--, carboxy, (2-quinolinyl)methoxy, oleyloxy,linoleyloxy, R₈ OOC(CH₂)₀ O--, R₆ [O(CH₂)₂ ]_(q) O--, R₇ (CH₂)_(p) O--;

R₅ is CH₃ (CH₂)_(n) --, 1-adamantyl or diphenylmethyl;

R₆ is lower alkyl;

R₇ is 1- or 2-naphthyloxy, 1-, 2- or 3-pyridinyloxy, 2,3- or3,4-dihydroxyphenyl, 6,7-dihydroxy-2-naphthyl, phenyl, phenoxy orsubstituted phenyl or phenoxy, wherein the substituent is selected fromthe group consisting of lower alkyl, lower alkoxy, hydroxy, nitro,amino, halo, R₆ S(O)₀₋₂ --, carboxy, carboxy-lower alkyl or phenyl;

R₈ is hydrogen or lower alkyl;

n is an integer from 0 to 17;

m is an integer from 1 to 3;

o is an integer from 1 to 10;

p is an integer from 2 to 18, and

q is an integer from 1 to 6;

and, when R₂ is hydrogen, pharmaceutically acceptable salts thereof withbases.

The compounds of formula 1 are potent inhibitors of phospholipases A₂(PLA₂ 's) and are therefore useful in the treatment of inflammatorydisease, such as psoriasis, inflammatory bowel disease, asthma, allergy,arthritis, dermatitis, gout, pulmonary disease, myocardial ischemia, andtrauma induced inflammation, such as spinal cord injury.

In another aspect, the invention relates to compositions and methods ofuse comprising the compounds of formula 1.

BACKGROUND OF THE INVENTION

Phospholipases A₂ (PLA₂ 's) are a class of enzymes which catalyze thehydrolysis of membrane phospholipids at the sn-2 position leading tofree fatty acids and lysophospholipid. Arachidonic acid is stored in thecell membrane as an ester almost exclusively at the 2-position ofphospholipids. PLA₂ acts to release arachidonic acid from phospholipidsin what is believed to be the rate controlling step which ultimatelyleads to the products of the arachidonic acid cascade. Free arachidonicacid is rapidly metabolized by cyclooxygenase to give prostaglandins andthromboxane or by lipoxygenases to form hydroxy fatty acids andleukotrienes. Prostaglandins and leukotrienes are important mediators ofinflammation and hydroxy fatty acids such as leukotriene B₄ act aschemotactic agents for neutrophils and eosinophils and may cause cellmigration to sites of inflammation. Lysophospholipids are cytotoxic andhave also been implicated in several inflammatory conditions. Inaddition, platelet activating factor (PAF) can be formed by the actionof an acetyl transferase on a 1-alkyl-2-lysophospholipid. PAF is apotent platelet aggregating substance and causes various inflammatoryconditions such as erythema, vascular permeability and cellularchemotaxis. These facts provide support for the utilization of aninhibitor of PLA₂ 's as therapy for various inflammatory conditions.

DETAILED DESCRIPTION OF THE INVENTION ##STR3## wherein R₁ is hydrogen or--(CH₂)_(m) COOR₂ ;

R₂ is hydrogen, (R₆)₂ N(CH₂)₂ --, R₆ COOCH₂ -- or --CH₂ CON(CH₂ CH₂ OH)₂;

R₃ is hydrogen, nitro, hydroxy, amino, CH₃ (CH₂)_(n) S(O)₀₋₂ --, CH₃(CH₂)_(n) --, CH₃ (CH₂)_(n) O--, R₅ COO--, R₅ OOC--, R₅ HNCOO--, R₅NHCO--, R₅ CONH--, R₅ NHCONH--, [CH₃ (CH₂)_(n) ]₂ NCO--, CH₃ (CH₂)_(n)CHOHCH₂ O--, (2-quinolinyl)methoxy, oleyloxy, linoleyloxy, R₈ OOC(CH₂)₀O--, (R₆ O)₂ PO(CH₂)_(p) O--, (HO) (R₆ O)PO(CH₂)_(p) O--, R₆ [O(CH₂)₂]_(q) O--, R₇ (CH₂)_(p) O--, or --O(CH₂)_(p) --pyridinium⁺ (OH--);

R₄ is CH₃ (CH₂)_(n) --, CH₃ (CH₂)_(n) O--, CF₃ SO₂ NH--, R₅ COO--, R₅OOC--, R₅ HNCOO--, R₅ NHCO--, R₅ NHCONH--, [CH₃ (CH₂)_(n) ]₂ NCO--, CH₃(CH₂)_(n) CHOHCH₂ O--, carboxy, (2-quinolinyl)methoxy, oleyloxy,linoleyloxy, R₈ OOC(CH₂)₀ O--, R₆ [O(CH₂)₂ ]_(q) O--, R₇ (CH₂)_(p) O--;

R₅ is CH₃ (CH₂)_(n) --, 1-adamantyl or diphenylmethyl;

R₆ is lower alkyl;

R₇ is 1- or 2-naphthyloxy, 1-, 2- or 3-pyridinyloxy, 2,3- or3,4-dihydroxyphenyl, 6,7-dihydroxy-2-naphthyl, phenyl, phenoxy orsubstituted phenyl or phenoxy, wherein the substituent is selected fromthe group consisting of lower alkyl, lower alkoxy, hydroxy, nitro,amino, halo, R₆ S(O)₀₋₂ --, carboxy, carboxy-lower alkyl or phenyl;

R₈ is hydrogen or lower alkyl;

n is an integer from 0 to 17;

m is an integer from 1 to 3;

o is an integer from 1 to 10;

p is an integer from 2 to 18, and

q is an integer from 1 to 6;

and, when R₂ is hydrogen, pharmaceutically acceptable salts thereof withbases.

As used herein, the term "lower alkyl", alone or in combination, denotesa straight or branched chain saturated hydrocarbon containing 1 to 7carbon atoms, preferably from 1 to 4 carbon atoms, for example, methyl,ethyl, propyl, isopropyl, butyl, dimethylethyl, neopentyl, pentyl,heptyl, and the like. The term "lower alkoxy" denotes an alkyl ethergroup in which the alkyl group is as described above, for example,methoxy, ethoxy, propoxy, pentoxy and the like.

The term "halogen" denotes all the halogens, for example, bromine,chlorine, fluorine and iodine.

A preferred group of compounds of formula 1 are those wherein R₁ is--(CH₂)_(m) COOR₂.

Still other preferred compounds of formula 1 are those wherein R₁ is--(CH₂)_(m) COOR₂ ; and R₂ is hydrogen.

Preferred compounds of formula 1 are also those wherein R₁ is--(CH₂)_(m) COOR₂, m is 1-2, R₃ and R₄ are the same and are CH₃(CH₂)_(n) O-- or CH₃ (CH₂)_(n) NHCO--, n is 3-17 and the substitutionpattern is ##STR4##

Another preferred group of compounds of formula 1 are those wherein R₁is --(CH₂)_(m) COOR₂ and m is 1-2 and R₃ is CH₃ (CH₂)_(n) O--, wherein nis 3-17 and R₄ is selected from the group consisting of R₈ OOC(CH₂)₀ O,R₆ [O(CH₂)₂ ]_(q) O--, R₇ (CH₂)_(p) O--, R₅ OOC-- and CF₃ SO₂ NH-- andthe substitution pattern is 1, 3, 5.

More preferred compounds of formula 1 are those wherein R₁ is HOOCCH₂--, m is 1, R₂ is hydrogen and R₃ and R₄

(a) are both CH₃ (CH₂)_(n) O-- or CH₃ (CH₂)_(n) NHCO-- wherein n is 3-17and the substitution pattern is 1,3,5 or 1,3,4, or

(b) R₄ is CH₃ (CH₂)_(n) O-- wherein n is 9-17 and R₃ is hydrogen and thesubstitution pattern is 1,3, or

(c) R₃ is CH₃ (CH₂)_(n) O-- wherein n is 9-17 and R₄ is R₈ OOC(CH₂)₀ O--wherein o is 1-6, R₇ (CH₂)_(p) O-- wherein R₇ is 2,3-dihydroxyphenyl orsubstituted phenoxy and p is 2-10, carboxy, CF₃ SO₂ NH-- or R₆ [O(CH₂)₂]_(q) O-- wherein q is 2-5 and the substitution pattern is 1,3,5.

Most preferred compounds of formula 1 are those wherein R₁ is HOOCCH₂--, R₂ is hydrogen, m is 1, R₃ and R₄

(a) are both CH₃ (CH₂)_(n) O-- wherein n is 7-13 and the substitutionpattern is 1,3,5 or

(b) R₃ is C₁₈ H₃₇ O-- and R₄ is R₈ OOC(CH₂)₀ O-- wherein R₈ is hydrogenor methyl and o is 1-4, carboxy, CF₃ SO₂ NH--, R₆ [O(CH₂)₂ ]_(q) O--wherein q is 2-3, R₇ (CH₂)pO-- wherein R₇ is 2,3-dihydroxyphenyl orunsubstituted or substituted phenoxy wherein the substituent is selectedfrom the group consisting of lower alkoxy, hydroxy, nitro, amino,methylsulfinyl or methylsulfonyl and p is 3-6 and the substitutionpattern is 1, 3, 5.

The preferred compounds of the invention are:

N-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3,5-bis(dodecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3,5-bis(tetradecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]glycine;

N-[3-(4-carboxybutoxy)-5-(octadecyloxy)phenyl]-N-(carboxymethyl)glycine;

N-(carboxymethyl)-N-[3-(octadecyloxy)-5-(3-phenoxypropoxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(3-methoxyphenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(4-methoxyphenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(4-hydroxyphenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(3-nitrophenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(3-aminophenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-(methoxycarbonyl)-5-(octadecyloxy)phenyl]glycine;

N-[3-carboxy-5-(octadecyloxy)phenyl]-N-(carboxymethyl)glycine;

N-(carboxymethyl)-N-[3-[3-[4-(methylsulfonyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[5-(2,3-dihydroxyphenyl)pentoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[4-(2,3-dihydroxy-6-naphthalenyl)butoxy]-5-(octadecyloxy)phenyl}glycine;and

N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[[(trifluoromethyl)sulfonyl]amino]phenyl]glycine.

Exemplary of other compounds of the invention are:

N-(carboxymethyl)-N-[3,5-bis(undecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3,5-bis(nonyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3,5-bis(tridecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3,5-bis[(dodecylamino)carbonyl]phenyl]glycine;

N-(carboxymethyl)-N-[3,5-bis[(octylamino)carbonyl]phenyl]glycine;

N-(carboxymethyl)-N-3,5-bis[(1-oxododecyl)amino]glycine;

N-(carboxymethyl)-N-3,5-bis[(1-oxotetradecyl)amino]glycine;

N-(carboxymethyl)-N-(3,5-dioctylphenyl)glycine;

N-(carboxymethyl)-N-(3,5-didodecylphenyl)glycine;

N-(carboxymethyl)-N-[3,5-bis[(1-oxooctyl)oxy]phenyl]glycine;

N-(carboxymethyl)-N-[3,5-bis[(1-oxododecyl)oxy]phenyl]glycine;

N-(carboxymethyl)-N-[3,5-bis[(octyloxy)carbonyl]phenyl]glycine;

N-(carboxymethyl)-N-[3,5-bis[(dodecyloxy)carbonyl]phenyl]glycine;

N-(carboxymethyl)-N-[[3-(octadecyloxy)-5-(1-oxopentyl)oxy]phenyl]glycine;

N-(carboxymethyl)-N-[[3-(octadecyloxy)-5-(1-oxononyl)oxy]phenyl]glycine;

N-(carboxymethyl)-N-[[3-(octadecyloxy)-5-(1-oxoundecyl)oxy]phenyl]glycine;

N-(carboxymethyl)-N-[3-(octadecyloxy)-5-(3-phenoxypentyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-(octadecyloxy)-5-(3-phenoxyethoxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-(tetradecyloxy)-5-(3-phenoxypentyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-(decyloxy)-5-(3-phenoxypentyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-(octadecyloxy)-4-(3-phenoxypentyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-(octadecyloxy)-4-(3-phenoxypropoxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-[3-(methylsulfinyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-[2-(methylsulfinyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(2-methoxyphenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(4-nitrophenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(2-nitrophenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(3-hydroxyphenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(2-hydroxyphenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(4-aminophenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(2-aminophenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(2,3-dihydroxyphenyl)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[3-(3,4-dihydroxyphenyl)propoxy]-5-(octadecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[5-(2,3-dihydroxyphenyl)pentoxy]-5-(tetradecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[5-(2,3-dihydroxyphenyl)pentoxy]-5-(decyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[5-(2,3-dihydroxyphenyl)pentoxy]-4-(tetradecyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[3-[2-(2,3-dihydroxy-6-naphthalenyl)ethoxy]-5-(tetradecyloxy)phenyl}glycine;

N-(carboxymethyl)-N-[3-[4-(2,3-dihydroxy-6-naphthalenyl)butoxy]-5-(tetradecyloxy)phenyl}glycine;

N-(carboxymethyl)-N-[3-[4-(2,3-dihydroxy-6-naphthalenyl)butoxy]-4-(tetradecyloxy)phenyl}glycine;

N-(carboxymethyl)-N-[3-decyloxy-5-(3,6,9-trioxaundec-1-yloxy)phenyl]glycine;

N-(carboxymethyl)-N-[2,3-bis(decyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[2,4-bis(decyloxy)phenyl]glycine;

N-(carboxymethyl)-N-[2,5-bis(decyloxy)phenyl]glycine; and the like.

The compounds of formula 1 can be prepared as set forth in Schemes 1-16.##STR5## wherein R₂ ' is lower alkyl or benzyl and R₃, R₄, m are aspreviously described.

In Scheme 1 a substituted aniline of formula 2, which can be preparedaccording to one of the Schemes which follows, can be convened to thecorresponding compound of the invention by a two step process. In thefirst step an aniline of formula 2 is convened to the correspondingdialkylated aniline of formula 3 by reaction with an excess of a bromoester in the presence of a base such as1,8-bis(dimethylamino)naphthalene (Proton Sponge) or an alkali metalcarbonate in an anhydrous, polar, aprotic solvent such as acetonitrile,acetone or dimethylformamide (DMF) or mixtures thereof. The reaction iscarried out at a temperature of from 56°-100°. Sodium iodide is usuallyadded to facilitate the reaction. Alternatively, a compound of formula 2can be convened to the corresponding monoalkylated aniline of formula 4under similar reaction conditions but without using a large excess ofthe bromo ester. Intermediates of formulas 3 and 4 can be converted tothe corresponding compounds of the invention of formula 1a and 1b byhydrolysis using an alkali metal hydroxide in a solvent mixture of waterand a lower alkanol. In some cases, a co-solvent such as dioxane must beadded to improve solubility. Hydrogenolysis can also be used forconversion of a compound of the formula 3 or 4 to the correspondingcompound of formula 1a or 1b when the R₂ ' group is benzyl. This isaccomplished by shaking a solution of a compound of formula 3 or 4 witha palladium catalyst in a hydrogen atmosphere using an inert solventsuch as ethyl acetate, tetrahydrofuran (THF) or DMF.

The substituted anilines of formula 2 required for the preparation ofthe compounds of the invention can be prepared as set forth in Schemes2-9. ##STR6## wherein R₃ ^(a) and R₄ ^(a) are the same, and are CH₃(CH₂)_(n) O--, R₆ OOC(CH₂)₀ O--, oleyloxy, linoleyloxy, R₆ [O(CH₂)₂]_(q) O--, R₇ (CH₂)_(p) O-- or CH₃ (CH₂)_(n) CHOHCH₂ O--, R₆ and R₇ areas previously described, R' is benzyl or methyl, and R" is benzyl ort-butyl.

The process of Scheme 2 can be used for the preparation of disubstitutedanilines of formula (2a) wherein R₃ ^(a) and R₄ ^(a) are the same. Aknown dihydroxy ester of formula 5 can be dialkylated to give thecorresponding compound of formula 6 by heating with excess of thecorresponding alkyl halide or epoxide using an alkali metal carbonate asa base in a solvent such as acetone or DMF or mixes thereof. The esterof formula 6 can be hydrolyzed to the corresponding acid of formula 7under standard conditions using an alkali metal hydroxide in a solventmixture of water and a lower alkanol with added dioxane to improvesolubility, if needed. A benzoic acid of formula 7 can be convened tothe corresponding carbamate of formula 8 using the Curtius Reactionunder the following conditions. An acid of formula 7 is converted to thecorresponding acyl azide using diphenylphosphoryl azide in an inert,anhydrous solvent such as toluene or benzene in the presence of atertiary amine such as triethylamine at temperatures of from 0°-30°.Heating the acyl azide solution at 60°-110° causes rearrangement to thecorresponding isocyanate. Addition of benzyl alcohol or t-butyl alcoholfollowed by continued heating at 60°-110° results in formation of thecorresponding carbamic acid benzyl ester or t-butyl ester of formula 8.The conversion of a compound of formula 7 to the corresponding compoundof formula 8 can also be carried out by heating a compound of formula 7,diphenylphosphoryl azide and triethylamine in t-butyl alcohol at60°-83°. Finally, a carbamate of formula 8 can be convened to thecorresponding disubstituted aniline of formula 2a by hydrogenolysis, ifR" is benzyl, carried out by shaking with a palladium catalyst in ahydrogen atmosphere in an inert solvent such as ethyl acetate or THF. Acarbamate of formula 8, if R" is t-butyl, is convened to thecorresponding compound of formula 2a by treatment with trifluoroaceticacid in a solvent such as methylene chloride at a temperature of from0°-30°. ##STR7## wherein R₃ ^(b) and R₄ ^(b) are different, and are CH₃(CH₂)_(n) O--, R₅ COO--, R₅ HNCOO--, oleyloxy, linoleyloxy, R₆ [O(CH₂)₂]_(q) O--, R₆ OOC(CH₂)₀ O--, R₇ (CH₂)_(p) O-- or CH₃ (CH₂)_(n) CHOHCH₂O--, R' is benzyl or methyl or R" is benzyl or t-butyl.

The process of Scheme 3 can be used for the preparation of disubstitutedanilines of formula 2b, wherein R₃ ^(b) and R₄ ^(b) are different. Aknown dihydroxy ester of formula 5 can be monoalkylated by heating withan equimolar amount of the corresponding alkyl halide using an alkalimetal carbonate as the base in a solvent such as acetone or DMF or mixesthereof. The desired monoalkylation product of formula 9 can beseparated from the dialkylation product and the starting material offormula 5 using standard separation techniques. Alkylation of a compoundof formula 9 using the same conditions but with a different alkylbromide then provides the corresponding compound of formula 10 which canbe hydrolyzed or hydrogenolyzed to the corresponding acid of formula 11.An acid of formula 11 is subjected to the Curtius Reaction to give thecorresponding carbamate 12, which can be converted to the disubstitutedaniline of formula 2b, as described in Scheme 2. ##STR8## wherein X andY are the same, and are OH or NH₂, R₃ ^(c) and R₄ ^(c) are the same, andare R₅ COO--, R₅ NHCOO--, R₅ CONH-- or R₅ NHCONH--, R₅ is as previouslydescribed, and R" is benzyl or t-butyl.

In Scheme 4, a known dihydroxy or diaminobenzoic acid of formula 13 canbe convened to the corresponding compound of formula 14 by treatmentwith the corresponding acid chloride or isocyanate in the presence of atertiary amine such as triethylamine and a solvent such as methylenechloride or THF at a temperature of from 0°-30°. The resulting acid offormula 14 when subjected to the Curtius Reaction under conditionsdescribed earlier provides the corresponding carbamate of formula 15which can be convened to the substituted aniline of formula 2c, as inScheme 2. ##STR9## wherein R₃ ^(d) and R₄ ^(d) are the same, and are R₅OOC--, R₅ NHCO-- or [CH₃ (CH₂)_(n) ]₂ NCO--, and R₅ is as previouslydescribed.

In Scheme 5, a known dicarboxylic acid of formula 16 is convened to thecorresponding diacid chloride of formula 17 by heating with thionylchloride. Treatment of a compound of formula 17 with the correspondingalcohol or primary or secondary amine in the presence of a tertiaryamine such as triethylamine in an inert solvent such as methylenechloride or THF at a temperature of from 0°-30° provides thecorresponding compound of formula 18. Catalytic hydrogenation of acompound of formula 18 using a palladium catalyst in a solvent such asethyl acetate or THF gives the corresponding substituted aniline offormula 2d. ##STR10## wherein n is as previously described.

In Scheme 6, a known dialdehyde of formula 19 is treated at 0°-30° withthe corresponding Wittig reagent prepared under standard conditions(alkyl triphenylphosphonium bromide, alkyl lithium in THF at 0°) to givethe corresponding mixture of (Z) and (E) isomers of formula 20.Hydrogenation of the double bonds using standard conditions, palladiumcatalyst in THF under hydrogen pressure, provides the correspondingsubstituted aniline of formula 2e. ##STR11## wherein R₃ ^(e) and R₄ ^(e)are identical, and are CH₃ (CH₂)_(n) O--, CH₃ (CH₂)_(n) CHOHCH₂ O--, R₅COO--, R₅ HNCOO--, R₆ [O(CH₂)₂ ]_(q) O--, R₆ OOC(CH₂)₀ O--, or R₇(CH₂)_(p) O--, and R₅, R₆ and R₇ are as previously described.

In Scheme 7, a known dihydroxy compound of formula 21 is alkylated bytreatment with the corresponding alkyl halide in the presence of analkali metal carbonate in a solvent such as acetone or dimethylformamideor mixtures thereof at a temperature of from 56°-100° to give thecorresponding compound of formula 22.

A compound of formula 21 can also be treated with the corresponding acidchloride or isocyanate in the presence of an organic base such aspyridine or triethylamine in a solvent such as methylene chloride or THFat temperature of from 0°-50° to give the corresponding bis ester offormula 22 or the corresponding bis carbamate of formula 22. Catalytichydrogenation of a compound of formula 22 using a palladium catalystunder standard conditions in a solvent such as ethyl acetate or THFgives the corresponding substituted aniline 2f. ##STR12## wherein X isOH or NH₂, R₃ ^(f) is CH₃ (CH₂)_(n) O--, CH₃ (CH₂)_(n) CHOHCH₂ l O--, R₅COO--, R₅ NHCOO--, R₅ CONH--, R₅ NHCONH--, R₆ [O(CH₂)₂ ]_(q) O-- or R₇(CH₂)_(p) --, and n, q, p, R₅, R₆ and R₇ are as previously described

In Scheme 8, a known nitro phenol or nitro aniline of formula 23 istreated with the corresponding alkyl halide, acid chloride or isocyanateunder conditions described in Scheme 7 to give the correspondingcompound of formula 24 which can be converted to the correspondingsubstituted aniline of formula 2g, using standard catalytichydrogenation conditions. ##STR13## wherein R₃ ^(d) is as previouslydescribed.

In Scheme 9, a known nitro acid chloride of formula 25 is treated withthe corresponding primary or secondary amine or an alcohol in thepresence of a base such as triethylamine in a solvent such as methylenechloride or THF at temperatures of from 0°-30° to give the correspondingcompound of formula 26. Catalytic hydrogenation serves to convert acompound of formula 26 to the corresponding substituted aniline offormula 2h. ##STR14## wherein R₃ ^(a) and R₄ ^(a) are the same, and areas previously described and Bn is benzyl.

Schemes 10-16 illustrate alternative methods to prepare compounds of theinvention. In Scheme 10, a known dihydroxy ester of formula 27 isconverted to the corresponding bis benzyl ether of formula 28 byalkylation with benzyl bromide under standard conditions and then to thecorresponding acid of formula 29 by base hydrolysis. A compound offormula 29 is subjected to the Curtius Reaction under conditionsdescribed earlier to give the corresponding compound of formula 30 whichis treated with trifluoroacetic acid to yield the corresponding compoundof formula 31. Treatment of a compound of formula 31 with excess methylbromoacetate under conditions described in Scheme 1 gives thecorresponding compound of formula 32. Catalytic hydrogenolysis of theresulting compound of formula 32 under standard conditions provides thecorresponding compound of formula 33 which can be converted to thecorresponding compound of formula 34 and then to 1c under conditionsdescribed in earlier Schemes. ##STR15## wherein R₃ ^(a) is as previouslydescribed and Bn is benzyl.

The monosubstituted compounds of the invention of formula (1d) can beprepared from the known benzyloxy anilines of formula (35) as shown inScheme 11 using conditions described in earlier Schemes. ##STR16##wherein R₃ ^(g) is R₅ CONH-- or R₅ NHCONH--, and R₅ is as previouslydescribed.

In Scheme 12, a known nitro aniline of formula 39 can be converted tothe corresponding compound of formula 40 by heating with excess methylbromoacetate in the presence of a tertiary amine such asdiisopropylethyl amine in a solvent such as acetonitrile or DMF, attemperatures of from 80°-110° followed by catalytic hydrogenation usinga palladium catalyst under standard conditions. Treatment of a compoundof formula 40 with the corresponding acid chloride or isocyanate in thepresence of a tertiary amine such as triethylamine in a solvent such asmethylene chloride at temperatures of from 0°-30° gives thecorresponding compound of formula 41 which on base hydrolysis using analkali metal hydroxide in a solvent mixture of water and a loweralkanol, with added dioxane to improve solubility in some cases, givesthe corresponding compound of formula 1e. ##STR17## wherein R₃ ^(e) andR₄ ^(e), are different, and Bn is benzyl.

Compounds of formula 1f of the invention, wherein R₃ ^(e) and R₄ ^(e)are different, can also be prepared according to Scheme 13. A compoundof formula 42 prepared according to Scheme 3 is convened to thecorresponding benzyl ester of formula 43 and then to the correspondingacid of formula 44, t-butyl carbamate of formula 45 and aniline offormula 46, under the usual conditions. Alkylation of a compound offormula 46 with methyl bromoacetate, as described in Scheme 1, gives thecorresponding compound of formula 47 from which the benzyl ether can beremoved using catalytic hydrogenolysis to give the correspondingcompound of formula 48. A different group can now be introduced bytreatment with the corresponding alkyl bromide in the presence of analkali metal carbonate such as potassium carbonate in a solvent such asacetone or DMF or mixtures thereof at a temperature of from 56°-100° togive the corresponding compound of formula 49. Base hydrolysis with analkali metal hydroxide gives the corresponding compound of the inventionof formula 1f. ##STR18## wherein R₃ ^(h) is CH₃ (CH₂)_(n) O--, R₇(CH₂)_(p) O-- or R₆ [O(CH₂)₂ ]_(q) O--, R₄ ^(h) is R₅ CONH-- or R₅NHCONH--, and n, p, q, R₅, R₆ and R₇ are as defined previously.

In Scheme 14, a compound of formula 50, which is described in theExamples, can be converted by the Curtius Reaction to the correspondingcarbamate of formula 51 and then by treatment with trifluoroacetic acidto the corresponding compound of formula 52 as described in earlierSchemes. Alkylation of the resulting compound of formula 52 with methylbromoacetate under the usual conditions gives the corresponding compoundof formula 53 which on base hydrolysis provides the compound of formula1g. Catalytic hydrogenation of the resulting compound of formula 1gunder standard conditions gives the corresponding compound of formula1h. Treatment of a compound of formula 52 with the corresponding acidchloride or isocyanate and triethylamine as described in previousSchemes gives the corresponding compound of formula 54, which oncatalytic hydrogenation followed by reaction with excess benzylbromoacetate and finally catalytic hydrogenolysis gives thecorresponding compound of formula 1i. ##STR19## wherein R₃ ^(h), R₅ andR₆ are as previously described, Bn is Benzyl and p is 2-12.

In Scheme 15, a compound of formula 55, which is described in theExamples which follow, can be alkylated with excess of the correspondingdibromoalkane using potassium carbonate as the base in a solvent such asacetone or DMF or mixtures thereof at temperatures of from 56°-100° togive the corresponding compound of formula 56. The Arbusov Reactionunder standard conditions using triethyl phosphite at 150° serves toconvert a compound of formula 56 to the corresponding compound offormula 57. Removal of the benzyl group by catalytic hydrogenolysis gavethe corresponding compound of formula 58 which was convened using theCurtius Reaction via the corresponding benzyl carbamate of formula 59followed by catalytic hydrogenolysis to the corresponding compound offormula 60. Alkylation of a compound of formula 60 with excess benzylbromoacetate as described in earlier Schemes gives the correspondingcompound of formula 61 which, after catalytic hydrogenolysis, providesthe corresponding compound of formula 1j. Treatment of a compound offormula 1j with an alkali metal hydroxide in dimethylsulfoxide at100°-190° gives the corresponding compound of formula 1k. ##STR20##wherein R₃ ^(h) and Bn are as previously described.

In Scheme 16, the known compound of formula 62 is alkylated using thecorresponding alkyl bromide with potassium carbonate as a base underconditions described in earlier Schemes to give the correspondingcompound of formula 63. Catalytic hydrogenolysis of a compound offormula 63 carried out as usual gives the corresponding compound offormula 64 which can he alkylated with excess benzyl bromoacetate as inearlier Schemes to give the corresponding compound of formula 65.Hydrogenolysis of the latter as usual gives the corresponding compoundof formula 1m which can be hydrolyzed by heating at reflux with analkali metal hydroxide in a solvent mixture of water and a lower alkanolto provide the corresponding compound of formula 1n.

The invention also relates to salts of the compounds of formula 1 whenthey contain an acidic functionality, such as when R₂ is hydrogen, whichlends itself to salt formation with a base. Salts of the compounds offormula 1 which have a carboxy group are prepared by the reaction with abase having a non-toxic, pharmacologically acceptable cation. Ingeneral, any base which will form a salt with a carboxylic acid andwhose pharmacologically properties will not cause an adversephysiological effect is within the scope of this invention.

Suitable bases thus include, for example, the alkali metal and alkalineearth metal hydroxides, carbonates or the like, for example, calciumhydroxide, sodium hydroxide, sodium carbonate, potassium carbonate orthe like, ammonia, primary, secondary and tertiary amines, such as,monoalkylamines, dialkylamines, trialkylamines, for example,methylamine, diethylamine, triethylamine or the like, nitrogencontaining heterocyclic amines, for example, piperidine or the like. Asalt thus produced is the functional equivalent of the correspondingcompound of formula 1 wherein R₂ is hydrogen and one skilled in the artwill appreciate that the variety of salts embraced by the invention islimited only by the criterion that a base employed in forming thecorresponding salts be both non-toxic and physiologically acceptable.

The useful activity of the compounds of formula 1 as phospholipase A₂(PLA₂) inhibitors can be demonstrated as hereinafter set forth.

The compounds of formula 1 are potent inhibitors of phospholipases A₂(PLA₂ 's) and are therefore useful in the treatment of inflammatorydiseases, such as psoriasis, inflammatory bowel disease, asthma,allergy, arthritis, dermatitis, gout, pulmonary disease, myocardialischemia, and trauma induced inflammation, such as spinal cord injury.

Assay for Inhibition of HSF-PLA₂ In Vitro

The PLA₂ used in this test is the extracellular enzyme obtained fromhuman synovial fluid (HSF-PLA₂).

The assay for HSF-PLA₂ activity was a modification of the describedmethod [Franson R., Dobrow R., Weiss, J., Elsbach P., and Weglick W. B.,J. Lipid Res., 19, 18-23 (1978)] which was conducted using [1-¹⁴C]-oleate-labelled E. coli substrate in excess at a final concentrationof 20,000 dpm/ml. This was equivalent to 18.2 μM of cell membranephospholipid phosphorus and 2×10⁹ autoclaved E. coli/ml. The optimalconditions which were developed for the assay of HSF-PLA.sub. 2inhibitors are summarized as follows. A total volume of 0.5 ml ofreaction mixture typically had the following final composition:substrate (20,000 dpm/ml); enzyme (0.1% HSF, v/v); 2 mM CaCl₂ ; 150 mMNa⁺ ; 50 mM sodium HEPES buffer, pH 7.3; and 1% dimethyl sulfoxide(DMSO, used to solubilize test inhibitors) in the presence or absence ofinhibitor. The reaction was initiated by the addition of HSF-PLA₂ andduplicate samples of the mixture were incubated in 13×100 mm glass tubeswith shaking for 30 minutes at 37° C. The reaction was terminated by theaddition of 2.5 ml of chloroform-methanol (1 to 1.5, v/v). Theextraction of lipids from the stopped reaction mixture was conducted bythe further additions of 0.5 ml of chloroform and 1 ml of water withmixing. After centrifuging, the lower chloroform phase was transferredto smaller glass tubes and the solvent was evaporated to dryness with anitrogen stream. The extracted lipid residue was redissolved in 50 μl ofa solution containing carrier oleic acid (0.2 mg/ml) ofchloroform-methanol [9 to 1, v/v]). The whole lipid extract was appliedto a preactivated (30 minutes at 110° C.) silica gel-impregnated glassfiber thin layer chromatography sheet (ITLC type SG sheet from GelmanSciences Inc., Ann Arbor, Mich.) using hexane-acetic acid (100 to 1,v/v) as the developing solvent. This TLC system rapidly (6 minutes)resolved the enzymatically released product, ¹⁴ C-oleic acid, from theunreacted ¹⁴ C-phospholipid substrate. The unsaturated lipids werelocated on the chromatogram by a brief exposure to iodine vapor. Theoleic acid zone (R_(f) value 0.95) and phospholipid zone (origin) werecut out, chopped into small pieces, shaken with 2 ml of ethanol-water(80 to 20, v/v) and 15 ml of Aquasol and counted for radioactivity. Acontrol incubation of substrate in the absence of HSF-PLA₂ was performedin each experiment. The PLA₂ activity of the human synovial fluid wascorrected for this small control value. In the absence of inhibitors,these optimal conditions resulted in approximately 18% hydrolysis ofsubstrate (corrected for a substrate blank of <2%). The specificactivity of PLA₂ in the pooled human synovial fluid under the optimalassay conditions was 49.2 nmoles [1-¹⁴ C]-oleic acid released hour⁻¹mg⁻¹. The IC₅₀ (μM concentration of test compound that produces 50%inhibition of PLA₂ activity) was determined for each test compound. Theresults are reported in Table I.

Phospholipase A₂ Rat Paw Edema

Representative compounds of the invention were tested in rats todetermine their ability to inhibit the acute inflammatory responseinduced by the injection of snake venom phospholipase A₂. Test compoundsare administered intraperitoneally or orally to groups of seven Lewisrats (≈200 gm) 1 hr prior to phospholipase A₂ administration. The testcompounds are dissolved in dimethyl sulfoxide for intraperitonealadministration and dissolved or suspended in Labrafil M-1944CS for oraladministration. At 0 hr, 5 ug (10 units) of purified phospholipase A₂from Naja naja venom (Sigma Chem. Co.) dissolved in 0.1 mL of pyrogenfree saline is injected subplantarly into the right hind paw to elicitthe inflammatory response. The volume (in mL) of the right hind paw ismeasured by immersion of the paw to the level of the lateral malleolusin an aqueous plethysmometer immediately prior to the injection ofphospholipase A₂ and then at 0.5, 2 and 4 hr after phospholipase A₂injection. The paw edema is calculated by subtracting the zero timereading from the readings taken after injection. The percent change ofthe edema volume from the vehicle treated control is calculated todetermine the activity of the test compound. Statistical analysis of themean paw edema values of the control versus the treated groups isperformed using Student's t-test. Significance of changes from meanvalue for vehicle-treated animals (*p<0.05, **p<0.01, ***p<0.001, ns/notsignificant).

Croton Oil Mouse Ear Edema Test

The croton oil-induced mouse ear edema test, a model of irritant-inducedcontact dermatitis, has also been used for evaluation of the PLA₂inhibitors by the topical route of administration. This test was carriedout as described in the following references:

Weirich, E. G., Longauer, J. K and Kirkwood, A. A. Arch Dermatol. Res.259: 141-149, 1977.

Tubaro, A., Dri, P., Delbello, G., Zilli, C. and Della Loggia, R. Agentsand Actions, 17: 347-349, 1985.

The major active ingredient in croton oil is the tumor promoter12-O-tetradecanoylphorbol 13-acetate (TPA) and the topical applicationTPA to mouse skin has been reported to cause an increase in epidermalPGE₂ production as well as an increase in epidermal cell membrane PLA₂activity. Indomethacin, an inhibitor of prostaglandin synthesis,prevented the TPA-mediated increase in epidermal PGE₂ levels as well asthe TPA-mediated induction of epidermal cell ornithine decarboxylase.Furthermore, the application of PGE₂ to mouse skin countered theinhibitory effect of indomethacin upon TPA-stimulated cellularproliferation. Taken together these dam suggest that the croton oilmouse ear edema test is a valid model for the topical evaluation d PLA₂inhibitors.

Twenty five μl of a 1% croton oil solution [dissolved in a mixture ofpyridine/water/diethyl ether at a ratio of 5/20/75 (croton oilvehicle)]'are applied to the outer side of the right ear of 3-4 week oldmale CD-1 mice (8 animals per group). The test compounds are dissolveddirectly in the 1% croton oil solution at various concentrations andcoapplied. Control animals receive 25 μl of croton oil vehicle on theright ear. Biopsy punches are removed at 6 hours from the right ear ofthe animals using a 6 mm skin trephine (Roboz, Washington, D.C.) and thewet weight of the ear punches is determined. The weight of the biopsypunches is a measure of ear inflammation, primarily edema. The data areexpressed as percent inhibition relative to control groups.

The in vivo activity of representative compounds of formula 1 in thePLA₂ rat paw edema and the croton oil ear edema tests are reported inTable I.

                                      TABLE I                                     __________________________________________________________________________                                         % Inhib of                                                                    PLA.sub.2 Rat                                                                        % Inhib of                                                             Paw Edema                                                                            Croton Oil                                                       HSF-PLA.sub.2                                                                       2 hr (30                                                                             Mouse Ear                         Ex. No.                                                                            Name                      IC.sub.50 (μM)                                                                   mg/kg ip)                                                                            Edema (1 mg)                      __________________________________________________________________________    6a   N-[3,5-bis(butoxy)phenyl]-N-                                                                            2.0   33 ns  NT                                     (carboxymethyl)glycine                                                   6b   N-(carboxymethyl)-N-[3,5-bis                                                                            2.1   25 ns  NT                                     (hexyloxy)phenyl]glycine                                                 6c   N-(carboxymethyl)-N-[3,5-bis                                                                            0.4   +7 ns  0                                      (octyloxy)phenyl]glycine                                                 6    N-(carboxymethyl)-N-[3,5-bis                                                                             0.24 45***  13*                                    (decyloxy)phenyl]glycine                                                 6d   N-(carboxymethyl)-N-[3,5-bis                                                                             0.05 NT     21**                                   (dodecyloxy)phenyl]glycine                                               6e   N-(carboxymethyl)-N-[3,5-bis                                                                             0.13 44***  NT                                     (tetradecyloxy]phenyl]glycine   (50 mg/kg)                               6f   N-(carboxymethyl)-N-[3,5-bis                                                                            0.5   NT     NT                                     (octadecyloxy)phenyl]glycine                                             6g   N-(carboxymethyl)-N-[3,5-bis                                                                            1.3   26*    NT                                     (3-phenylpropoxy)phenyl]glycine                                          6h   rac-N-(carboxymethyl)-N-[3,5-bis                                                                        0.5    5 ns  NT                                     [[2-hydroxydecyl)oxy]phenyl]glycine                                      6i   N-(carboxymethyl)-N-[3,5-bis                                                                             6%   NT     NT                                     (5-hydroxy-5-oxopentyl)oxy]phenyl]glycine                                                               (20 μM)                                     6j   N-(carboxymethyl)-N-[3,5-bis[(11-methoxy-                                                               0.3   0      66***                                  11-oxoundecyl)oxy]phenyl]glycine                                         6k   N-(carboxymethyl)-N-[3,5-bis[(11-hydroxy-                                                               35%   0      16 ns                                  11 -oxoundecyl)oxy]phenyl]glycine                                                                       (10 μM)                                     6l   N-[3,5-bis[3-(1,1'-biphenyl-2-yloxy)propoxy]                                                             0.42 0      30**                                   N-(carboxymethyl)glycine                                                 6m   N-[3,5-bis[3-(1,1'-biphenyl-3-yloxy)propoxy]                                                             0.58 NT     NT                                     N-(carboxymethyl)glycine                                                 6n   N-[3,5-bis[3-(1,1'-biphenyl-4-yloxy)propoxy]                                                             0.40 NT     NT                                     N-(carboxymethyl)glycine                                                 6o   N-(carboxymethyl)-N-[3,5-bis[2-[2-                                                                      0.6   NT     NT                                     naphthalenyloxy)]ethoxy]glycine                                          6p   N-(carboxymethyl)-N-[3,5-bis[2-[1-                                                                      2.0   NT     NT                                     naphthalenyloxy)]ethoxy]glycine                                          16   N-(carboxymethyl)-N-[3,5-bis[(decyl-                                                                    0.3   0      10 ns                                  amino)carbonyl]phenyl]glycine                                            6q   N-(carboxymethyl)-N-[3,5-bis[(tetradecyl-                                                               0.3   0      NT                                     amino)carbonyl]phenyl]glycine                                            6r   N-(carboxymethyl)-N-[3,5-bis[(octadecyl-                                                                 0.64 NT     NT                                     amino)carbonyl]phenyl]glycine                                            6s   N-(carboxymethyl)-N-[3,5-bis[(tricyclo[3.3.1.1/3,                                                       30%   NT     NT                                     7/]phenyl]glycine         (10 μM)                                     21   N-(carboxymethyl)-N-[[3,5-bis[(1-oxo                                                                    3.8   NT     NT                                     decyl)amino)phenyl]glycine                                               29   N-(carboxymethyl)-N-(3,5-didecyl-                                                                       1.5   NT     NT                                     phenyl)glycine                                                           6t   N-(carboxymethyl)-N-(3,5-dinonadecyl-                                                                   39%   NT     NT                                     phenyl)glycine            (10 μM)                                     6u   N-(carboxymethyl)-N-[3,5-bis[(1-oxodecyl)                                                               64%   NT     NT                                     oxy]phenyl]glycine        (1 μM)                                      25   N-(carboxymethyl)-N-[3,5-bis[(tetradecyl-                                                               48%   17 ns  62***                                  oxy)carbonyl]phenyl]glycine                                                                             (1 μM)                                      6v   N-(carboxymethyl)-N-[3,5-bis[(decyl-                                                                    73%    9 ns  80***                                  oxy)carbonyl]phenyl]glycine                                                                             (1 μM)                                      119a N-(carboxymethyl)-N-[3,4-bis                                                                             0.16 NT     NT                                     (decyloxy)phenyl]glycine                                                 119  N-(carboxymethyl)-N-[3,4-bis                                                                            3 6%  16 ns  49***                                  (tetradecyloxy)phenyl]glycine                                                                           (1 μM)                                      123  N-(carboxymethyl)-N-(3,4-bis[(1-                                                                         0.48 4 ns   58***                                  oxodecyl)oxy]phenyl]glycine                                              119b N-(carboxymethyl)-N-[3,4-bis[(1-                                                                        80%   NT     75***                                  oxotetradecyl)oxy]phenyl]glycine                                                                        (1 μM)                                      119d N-(carboxymethyl)-N-[3,4-bis[[(octa-                                                                    19%   NT     14 ns                                  decylamino)carbonyl]oxy]phenyl]glycine                                                                  (1 μM)                                      119e N-(carboxymethyl)-N-[3,4-bis[[(tetra-                                                                   33%   NT     0                                      decylamino)carbonyl]oxy]phenyl]glycine                                                                  (1 μM)                                      36a  N-(carboxymethyl)-N-[3-(decyloxy)                                                                       2.9   35     NT                                     phenyl]glycine                                                           36   N-(carboxymethyl)-N-[3-(octa-                                                                            0.17 NT     21**                                   decyloxy)phenyl]glycine                                                  36b  N-(carboxymethyl)-N-3-[(1-oxoocta-                                                                      0.2   0      61***                                  decyl)oxy]phenyl]glycine                                                 36c  N-(carboxymethyl)-N-[3-[[(heptadecylamino)                                                              1.0   0      0                                      carbonyl]oxy] phenyl]glycine                                             36d  N-(carboxymethyl)-N-[[((decylamino)                                                                     4 6%  NT     NT                                     carbonyl]phenyl]glycine   (10 μM)                                     42   N-(carboxymethyl)-N-[3-[(octadecyl-                                                                     0.4   38**   0                                      amino)carbonyl]phenyl]glycine                                            174  N-(carboxymethyl)-N-[3-(di-decylamino)                                                                  74%   46**   29*                                    carbonyl)phenyl]glycine   (5 μM)                                      46   N-(carboxymethyl)-N-3-[(1-oxoocta-                                                                      84%   44**   35*                                    decyl)amino]phenyl]glycine                                                                              (5 μM)                                      36e  N-(carboxymethyl)-N-[3-[[(octadecylamino)                                                               74%   30*    31*                                    carbonyl]amino]phenyl]glycine                                                                           (5 μM)                                      49   N-(carboxymethyl)-N-[3-[(Z)-(9-octadecenyl)-                                                            0.3   NT     NT                                     oxy]phenyl]glycine                                                       49   N-(carboxymethyl)-N-[3-[(9Z,12Z)-(9,12-octa-                                                            0.2   NT     NT                                     decadienyl)oxy]phenyl]glycine                                            51   N-(carboxymethyl)-N-[3-[(Z)-(1-oxo-9-octadecenyl)                                                       63%   NT     NT                                     amino]phenyl]glycine      (5 μM)                                      51   N-(carboxymethyl)-N-[3-[(9Z,12Z)-(1-oxo-9,12-                                                           67%   NT     NT                                     octadecadienyl)amino]phenyl]glycine                                                                     (5 μM)                                      36f  N-(carboxymethyl)-N-(3-nonadecyl                                                                        0.2   NT     NT                                     phenyl)glycine                                                           36g  N-(carboxymethyl-N-[(3-(2-naphthalenyl-                                                                 19%   NT     NT                                     oxy)ethoxy]phenyl]glycine (10 μM)                                     36h  N-(carboxymethyl)-N-[3-[(tricyclo[3.3.1.1/3,7/]                                                         25%   NT     NT                                     dec-1-ylamino)carbonyl]phenyl]glycine                                                                   (20 μM)                                     36i  N-(carboxymethyl)-N-[3-(3-(3-pentadecylphenoxy)                                                         0.4    7 ns  NT                                     propoxy]phenyl]glycine                                                   39a  N-(carboxymethyl)-N-phenylglycine                                                                       -10%  NT     NT                                                               (20 μM)                                     39b  N-(carboxymethyl)-N-(4-butyl-                                                                           264   -9 ns  NT                                     phenyl)glycine                                                           39c  N-(carboxymethyl)-N-(4-octyl-                                                                           1.7   NT     NT                                     phenyl)glycine                                                           39d  N-(carboxymethyl)-N-(decyl-                                                                             39%   NT     NT                                     phenyl)glycine            (1 μM)                                      39   N-(carboxymethyl)-N-(4-tetra-                                                                           67%   NT     NT                                     decylphenyl)glycine       (1 μM)                                      80   N-[3-acetyloxy-5-(octadecyloxy)                                                                          0.22 NT     NT                                     phenyl]-N-(carboxymethyl)glycine                                         81   N-(carboxymethyl)-N-[3-hydroxy-5-                                                                        0.23 44***  69***                                  (octadecyloxy)phenyl]glycine    (10 mg/kg)                               58a  N-(carboxymethyl)-N-[3-(2-hydroxyethoxy)-                                                               0.2   29 ns   0                                     5-(octadecyloxy)phenyl]glycine                                           58b  N-(carboxymethyl)-N-[3-(2-methoxy-2-oxo-                                                                91%   20*    19*                                    ethoxy)-5-(octadecyloxy)phenyl]glycine                                                                  (5 μM)                                      58c  N-[3-(carboxymethoxy)-5-(octadecyloxy)                                                                  2.8   39***  0                                      phenyl]-N-(carboxymethyl)glycine                                         64   N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(5-                                                             0.06 61**   87***                                  methoxy-5-oxopentyl)oxy]phenyl]glycine                                   65   N-[3-(4-carboxybutoxy)-5-(octadecyloxy)                                                                  0.86 35*    91***                                  phenyl]-N-(carboxymethyl)glycine                                         58d  N-(carboxymethyl)-N-[3-(11-methoxy-11-oxo-                                                               0.08 NT     NT                                     undecyloxy)-5-(octadecyloxy)phenyl]glycine                               58e  N-(carboxymethyl)-N-[[3-(11-hydroxy-11-oxo-                                                             0.2   NT     NT                                     undecyloxy)phenyl]glycine                                                58f  N-(Carboxymethyl)-N-[[3-(octadecyloxy)-5-(tricyclo-                                                     0.3   NT     NT                                     [3.3.1.1/3,7]dec-1-ylcarbonyl)oxy]phenyl]glycine                         58g  N-(carboxymethyl)-N-3-(octadecyloxy)-5-(2,2-                                                            0.1   NT     NT                                     diphenyl-1-oxoethoxy)phenyl]glycine                                      58h  N-(carboxymethyl)-N-[3-[2-(2-naphthalenyloxy)                                                            0.05 31 ns   3 ns                                  ethoxy]-5-(octadecyloxy)phenyl]glycine                                   58i  N-(carboxymethyl)-N-3-(octadecyloxy)-5-[3-(3-                                                           0.3   NT     NT                                     pyridinyloxy)propoxy]phenyl]glycine                                      58   N-(carboxymethyl)-N-3-(octadecyloxy)-5-(3-                                                               0.06 36*    78***                                  phenoxy)phenyl]glycine                                                   58j  N-(carboxymethyl)-N-[3-[3-(3-methoxyphenoxy)                                                             0.06 57**   28*                                    propoxy]-5-(octadecyloxy)phenyl]glycine                                  58k  N-(carboxymethyl)-N-[3-[3-(4-methoxyphenoxy)                                                             0.05 0      85***                                  phenyl-5-(octadecyloxy)phenyl]glycine                                    58l  N-(carboxymethyl)-N-[3-[3-(4-hydroxyphenoxy)                                                            81%   53**   76***                                  propoxy]-5-(octadecyloxy)phenyl]glycine                                                                 (1 μM)                                      58m  N-(carboxymethyl)-N-[3-[3-(3-nitrophenoxy)                                                              79%   52**   60***                                  propoxy]-5-(octadecyloxy)phenyl]glycine                                                                 (1 μM)                                      58n  N-(carboxymethyl)-N-[3-[3-(3-aminophenoxy)                                                               0.13 4**    64***                                  propoxy]-5-(octadecyloxy)phenyl]glycine                                  58o  N-(carboxymethyl)-N-[3-[3-[4-(methoxycarbonyl)                                                          0.1   0      30*                                    phenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine                          58p  N-(carboxymethyl)-N-[3-[3-[4-(carboxy-                                                                  0.6   NT     0                                      phenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine                          108  N-[3-[3-(3-bromophenoxy)propoxy]-5-(octa-                                                               92%   12 ns  34*                                    decyloxy)phenyl]-N-(carboxymethyl)glycine                                                               (1 μM)                                      177  N-(carboxymethyl)-N-[3-[3-[4-(1,1-dimethylethyl)                                                        95%   41**   22 ns                                  phenoxy]propoxy-5-(octadecyloxy)phenyl]glycine                                                          (1 μM)                                      146  N-(carboxymethyl)-N-[3-[5-(2,3-dihydroxyphenyl)                                                         0.2   74**   18 ns                                  pentoxy]-5-(octadecyloxy)phenyl]glycine                                  88   N-(carboxymethyl)-N-[3-[3-(diethoxyphosphinyl)                                                          0.4   46**   43**                                   propoxy]-5-(octadecyloxy)phenyl]glycine                                  89   N-(carboxymethyl)-N-[3-[3-(ethoxyphosphinyl)                                                            31%   45**   NT                                     propoxy]-5-(octadecyloxy)phenyl]glycine                                                                 (1 μM)                                      151  N-(carboxymethyl)-N-[3-[2-[2-(2-                                                                        100%  43*    54***                                  ethoxyethoxy)ethoxy]ethoxy]-5-                                                                          (1 μM)                                           (octadecyloxy)phenyl]glycine                                             148  N-(carboxymethyl)-N-[(3-(octadecyloxy)-5-                                                               91%   37*    26*                                    [(2-quinolinyl)methoxy]phenyl]glycine                                                                   (1 μM)                                      154  N-(carboxymethyl)-N-[3-[4-(2,3-dihydroxy-6-                                                             9 6%  78**   NT                                     naphthalenylbutoxy]-5-(octadecyloxy)phenyl]glycine                                                      (1 μM)                                      156  N-(carboxymethyl)-N-[3-[2-[2-[2-(2-methoxyethoxy)                                                       100%  29**   NT                                     ethoxy]ethoxy]ethoxy]-5-(octadecyloxy)phenyl]glycine                                                    (1 μM)                                      159  N-(carboxymethyl)-N-[3-[3-[4-(methylsulfinyl                                                            100%  78**   59***                                  phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine                                                         (1 μM)                                      161  N-(carboxymethyl)-N-[3-[3-[4-(methylsulfonyl                                                            100%  66**   87***                                  phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine                                                         (1 μM)                                      69   N-(carboxymethyl)-N-[3-(methoxycarbonyl)-                                                               0.1   57**   22 ns                                  5-(octadecyloxy)phenyl]glycine                                           70   N-[3-carboxy-5-(octadecyloxy)phenyl]-N-                                                                 1.0   45**   0                                      (carboxymethyl)glycine                                                   75   N-(carboxymethyl)-N-[(3-carbamoyl)-                                                                     84%                                                 5-(octadecyloxy)phenyl]glycine                                                                          (5 μM)                                                                           33*    15 ns                             93   N-(carboxymethyl)-N-[3-nitro-                                                                           5 6%  20 ns  0                                      5-(octadecyloxy)phenyl]glycine                                                                          (1 μM)                                      94   N-(carboxymethyl)-N-[3-amino-                                                                            0.42 28 ns  10 ns                                  5-(octadecyloxy)phenyl]glycine                                           98   N-[3-(acetylamino)-5-(octadecyloxy)                                                                     98%   51**   NT                                     phenyl]-N-(carboxymethyl)glycine                                                                        (1 μM)                                      69a  N-(carboxymethyl)-N-[(3-methoxycarbonyl)-5-                                                             52%   12 ns  71***                                  (tetradecyloxy)phenyl]glycine                                                                           (1 μM)                                      69b  N-[3-carboxy-5-(tetradecyloxy)phenyl]-                                                                  18%   +4 ns  72***                                  N-(carboxymethyl)glycine                                                 69c  N-(carboxymethyl)-N-[(3-methoxycarbonyl)-5-                                                             22%    1 ns  78***                                  (decyloxy)phenyl]glycine                                                 69d  N-[3-carboxy-5-(decyloxy)phenyl]-                                                                        7%    0     63**                                   N-carboxymethyl)glycine   (1 μM)                                      162  N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[[trifluoro                                                     82%   65**   79***                                  methyl)sulfonyl]amino]phenyl]glycine                                                                    (1 μM)                                      166  N-(carboxymethyl)-N-[3-(methylthio)-5-                                                                  88%   31*    NT                                     octadecyloxy)phenyl]glycine                                              172  N-(carboxymethyl)-N-[3-(methylsulfinyl)-5-                                                              39%   43**   NT                                     octadecyloxy)phenyl]glycine                                                                             (1 μM)                                      186  [[3-[bis(carboxymethyl)amino]-5-(octadecyloxy)                                                          2 6%  45**   83***                                  phenyl]sulfinyl]acetic acid                                              12   N-[[3,5-bis[(decylamino)carbonyl]phenyl]glycine                                                         5.2   34**   70***                             127d rac-N-[[3,5-bis[(2-hydroxydecyl)oxy]phenyl]glycine                                                      3.5   NT     NT                                127c N-[3,5-bis(tetradecyloxy)phenyl]glycine                                                                 73%   NT     NT                                                               (10 μM)                                     125  N-[3-(octadecyloxy)phenyl]glycine                                                                       55%   NT     75***                                                            (10 μM)                                     175  N-[[3-(octadecyloxy)-5-(tricyclo[3.3.1.1/3,7/dec-                                                       0.3   NT     NT                                     1-ylcarbonyl)oxy]phenyl]glycine                                          30   4-[3,5-bis(decyloxy)phenyl]2,6-morpholinedione                                                           0.47 19 ns  63***                             31   N-(2-methoxy-2-oxoethyl)-N-[3,5-bis                                                                     9%    21 ns  50***                                  (decyloxy)phenyl]glycine                                                 32   N-(carbamoylmethyl)-N-[3,5-bis                                                                          48%   23 ns  54***                                  (decyloxy)phenyl]glycine ammonium salt                                   33   N-(2-diethylaminoethoxy-2-oxoethyl)-N-[3,5-bis                                                          -5%   15 ns  25*                                    (decyloxy)phenyl]glycine monohydrochloride salt                                                         ()1 μM)                                     132  N-2-[(acetyloxy)methoxy]-2-oxoethyl]-N-[3,5-bis                                                         NT    NT     36*                                    (decyloxy)phenyl]glycine(acetyloxy)methyl ester                          131  N-[3,5-bis(decyloxy)phenyl]-N-[2-[[bis(2-hydroxyethyl)                                                  NT    +18 ns 47***                                  amino]carbonyl]methoxy]-2-oxoethyl]glycine                                    [[bis(2-hydroxyethyl)amino]carbonyl]methyl ester                         130  N-[3,5-bis(decyloxy)phenyl]-N-[2-[2-(2-(diethylamino)                                                   NT    +2 ns  NT                                     ethoxy]-2-oxoethyl]glycine 2-(diethylamino)                                   ethylester hydrochloride                                                 __________________________________________________________________________

ASSAY FOR INHIBITION OF SNAKE VENOM PLA₂ (SV-PLA₂) IN VITRO

Several representative compounds of the invention were also tested asinhibitors of Naja naja snake venom PLA₂ (SV-PLA₂). The assay employedin this study was the spectrophotometric method described by: C. Vigo,G. P. Lewis and P. J. Piper in Biochemical Pharmacology, 29:623-627(1983), which was modified as described by: A. F. Welton, L. D. Tobias,C. Fiedler-Nagy, W. Anderson, W. Hope, K. Meyers and J. W. Coffey in"Plant Flavonoids in Biology and Medicine: Biochemical,Pharmacologically and Structure-Activity Relationships", p 231-242,(1986) Alan R. Liss, Inc. The PLA₂ paw-edema model, (data in Table I) isinitiated by injection of SV-PLA₂. The results obtained are set forth inTable II.

                  TABLE II                                                        ______________________________________                                                                      Inhib of                                                                      SV-PLA.sub.2                                    Ex. No. Name                  IC.sub.50 (μM)                               ______________________________________                                        6c      N-(carboxymethyl)-N-[3,5-bis                                                                        0.022                                                   (octyloxy)phenylglycine                                               6       N-(carboxymethyl)-N-[3,5-bis                                                                        0.017                                                   (decyloxy)phenylglycine                                               6d      N-(carboxymethyl)-N-[3,5-bis                                                                        0.17                                                    (dodecyloxy)phenylglycine                                             39c     N-(carboxymethyl)-N-(4-octyl-                                                                       0.066                                                   phenyl)glycine                                                        16      N-(carboxymethyl)-N-[3,5-bis(decyl-                                                                 0.05                                                    amino)carbonyl]phenyl]glycine                                         ______________________________________                                    

Rat Carrageenan Paw Edema

Representative compounds of the invention were tested in ratcarrageenan-induced paw edema to determine their ability to inhibit thisacute inflammatory response. Test compounds are administeredintraperitoneally or orally to groups of seven Lewis rats (≈200 gm) 1 hrprior to carrageenan administration. The test compounds are dissolved indimethyl sulfoxide for intraperitoneal administration and dissolved orsuspended in Labrafil M-19944CS for oral administration. At 0 hour, 0.1mL of 1% carrageenan dissolved in pyrogen free saline is injectedsubplantarly into the right hind paw to elicit the inflammatoryresponse. The volume (in mL) of the right hind paw is measured byimmersion of the paw to the level of the lateral malleolus in an aqueousplethysmometer immediately prior to the injection of carrageenan andthen at 1, 2 and 4 hr after carrageenan injection. The paw edema iscalculated by substracting the zero time reading from the readings takenafter injection. The percent change of the edema volume from the vehicletreated control is calculated to determine the activity of the testcompound. Statistical analysis of the mean paw edema values of thecontrol versus the treated groups are performed using Student's t-test.

The results obtained are set forth in Table III.

                                      TABLE III                                   __________________________________________________________________________    RAT CARRAGEENAN PAW TEST                                                                                        Dose % Inhibition                           Ex. No.                                                                            Name                         mg/kg in                                                                           at 2 hours                             __________________________________________________________________________    36a  N-(carboxymethyl)-N-[3-(decyloxy)                                                                          30    47***                                      phenyl]glycine                                                           64   N-(carboxymethyl)-N-[3-[3-(diethoxyphosphinyl)                                                             30   69**                                        methoxy-5-oxopentyl)oxy]phenyl]glycine                                   88   N-(carboxymethyl)-N-[3-[3-(diethoxyphosphinyl)                                                             30   57**                                        propoxy]-5-(octadecyloxy)phenyl]glycine                                  58   N-(carboxymethyl)-N-[3-[3-(octadecyloxy)-5-                                                                30   29**                                        (3-phenoxypropoxy)phenyl]glycine                                         58m  N-(carboxymethyl)-N-[3-[3-(3-nitrophenoxy)propoxy-                                                         10   61**                                        5-(octadecyloxy)phenyl]glycine                                           58n  N-(carboxymethyl)-N-[3-[3-(3-aminophenoxy)propoxy-                                                         30   65**                                        5-(octadecyloxy)phenyl]glycine                                           108  N-[3-[3-(3-bromophenoxy)propoxy]-5-(octadecyloxy)                                                          30   33**                                        phenyl]-N-(carboxymethylglycine                                          177  N-(carboxymethyl)-N-[3-[3-4-(1,1-dimethylethyl)phenoxy]                                                    30   57**                                        propoxy]-5-(octadecyloxy)phenyl]glycine                                  146  N-(carboxymethyl)-N-3-[5-(2,3-dihydroxyphenyl)pentoxy]-                                                    30   55**                                        5-(octadecyloxy)phenyl]glycine                                           154  N-(carboxymethyl)-N-[3-[4-(2,3-dihydroxy-6-naphthalenyl)                                                   30   70**                                        butoxy]-5-(octadecyloxy)phenyl]glycine                                   159  N-(carboxymethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]                                                      30   44**                                        propoxy]-5-(octadecyloxy)phenyl]glycine                                  161  N-(carboxymethyl)-N-[3-[3-[4-(methylsulfonyl)phenoxy]                                                      30   56**                                        propoxy]-5-(octadecyloxy)phenyl]glycine                                       N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[[(trifluoromethyl)                                                30   69**                                        sulfonyl]amino]phenyl]glycine                                            __________________________________________________________________________

Established Adjuvant Arthritis Test

Representative compounds of the invention were tested in the standardadjuvant arthritis model in rats, induced by Freunds complete adjuvant,as described by C. E. Brinckerhoff, J. W. Coffey and A. C. Sullivan,Science, 221, p. 756-758 (1983). The results obtained are set forth inTable IV.

                                      TABLE IV                                    __________________________________________________________________________    ESTABLISHED ADJUVANT ARTHRITIS TEST                                                                           Change in Paw                                                            Dose Volume (mL)                                   Ex. No                                                                            Name                   mg/kg ip                                                                           Treated  Control                              __________________________________________________________________________    6   N-(carboxymethyl)-N-[3,5-bis                                                                         30    0.04 ±  0.24**                                                                     0.96                                     (decyloxy)phenyl]glycine                                                  58  N-(carboxymethyl)-N-[3-(octadecyloxy)-                                                               10   0.37 ± 0.14                                                                         0.60                                     5-(3-(phenoxypropoxy)phenyl]glycine                                       58m N-(carboxymethyl)-N-[3-[3-(3-nitrophenoxy)                                                           10    0.40 ±  0.13*                                                                      0.96                                     propoxy-5-(octadecyloxy)phenyl]glycine                                    58n N-(carboxymethyl)-N-[3-[3-(3-aminophenoxy)                                                           10    0.23 ± 0.12**                                                                      0.96                                     propoxy-5-(octadecyloxy)phenyl]glycine                                    88  N-(carboxymethyl)-N-[3-[3-(diethoxyphos-                                                             30    0.90 ± 0.11**                                                                      -0.28                                    phinyl)propoxy]-5-(octadecyloxy)phenyl]glycine                            89  N-(carboxymethyl)-N-[3-[3-(ethoxyphos-                                                               30    0.68 ± 0.08*                                                                       -0.28                                    phinyl)propoxy]-5-(octadecyloxy)phenyl]glycine                            70  N-[3-carboxy-5-(octadecyloxy)phenyl]-N-                                                              10    0.30 ± 0.09**                                                                      0.84                                     (carboxymethyl)glycine                                                    64  N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(5-                                                         10   0.65 ± 0.12                                                                         0.95                                     methoxy-5-oxopentyl)oxy]phenyl]glycine                                    151 N-(carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)-                                                       10    0.28 ± 0.16*                                                                       0.85                                     ethoxy]ethoxy]-5-(octadecyloxy)phenyl]glycine                             __________________________________________________________________________

Acetic Acid-Induced Colitis in Rats

The rat acetic acid-induced colitis bioassay has been described by J. E.Krawisz, et al. in Amer. J. Proc. Castro. Col. Rec. Surg. 31: 11-18(1980), and by P. Sharon and W. F. Stenson in Gastroenterology 88: 55-63(1985) and 86: 453-460 (1984). Acetic acid-induced colitis ischaracterized by the movement of inflammatory cells into the colon, withthe number of such cells in the mucosa being measured by the activity ofmyeloperoxidase, a marker enzyme for these cells. Positive desirableactivity is indicated by a reduction in the high levels ofmyeloperoxidase caused by acetic acid. Male rats (Sprague-Dawley),weighing 150 to 300 g, were pretreated twice daily for two days witheither the vehicle (water, or dimethylsulfoxide) or the test inhibitorcompound suspended in water or dissolved in dimethylsulfoxide and orallyadministered. On the third day, the animals were dosed the same as onthe previous two days, anesthetized with metofane, and 2 ml of 2.5%acetic acid was injected..by syringe into the colonic lumen, followedimmediately by 3 ml of air and a rinse consisting of 3 ml ofphosphate-buffered saline (the acetic acid is present in the lumen for asufficient period to cause inflammation without producing severenecrosis or irreversible damage). The animals were administered a seconddose of the test compound in the same amount about 16 hours later. Then24 hours after the acetic acid treatment, the animals were sacrificed.The colonic mucosa was surgically removed and homogenized in an aqueousbuffer at pH 6 with a Tissumizer or similar device and myeloperoxidasewas measured in the homogenate using o-phenylenediamine as a cromagen,as described by A. Voller, D. E. Bidwell and A. Bartlett in "The EnzymeLinked Immunosorbent Assay (ELISA)", Zoological Soc., London, 1979,pages 29-30. Control animals were pretreated with the vehicle and salinein place of acetic acid.

Data for representative compounds of this invention is reported in TableV.

                  TABLE V                                                         ______________________________________                                        RAT ACETIC ACID COLITIS TEST                                                                                % Inhibition                                                                  of Myeloper-                                                                  oxidase Ac-                                     Ex.                           cumulation at                                   No.  Name                     10 mg/kg po                                     ______________________________________                                        16   N-(carboxymethyl)-N-[3,5-bis[(decylamino                                                               212 ± 124                                         carbonyl]phenyl]glycine                                                  36   N-(carboxymethyl)-N-[3-(octadecyloxy)                                                                  190 ± 76                                          phenyl]glycine                                                           6e   N-(carboxymethyl)-N-[3,5-bis(tetradecyloxy)                                                            145 ± 72                                          phenyl]glycine                                                           ______________________________________                                    

In practice of the invention, the dose of a compound of formula 1 or asalt thereof to be administered and the frequency of administration willbe dependent on the potency and duration of activity of the particularcompound of formula 1 or salt to be administered and on the route ofadministration, as well as the severity and nature of the condition andage of the mammal to be treated and the like. Oral doses of a compoundof formula 1 or a salt thereof contemplated for use in practicing theinvention can be in the range of from 10 mg to about 2.0 g per day,preferably about 50 mg to about 1 gm per day, either as a single dose orin divided doses.

A compound of formula 1, or a salt or a composition containing atherapeutically effective mount of a compound of formula 1, (anenantiomer of a racemate, where applicable) or a salt thereof can beadministered by methods well known in the art. Thus, a compound offormula 1, or a salt thereof can be administered either singly or withother pharmaceutical agents, for example, antihistamines, mediatorrelease inhibitors, methyl xanthines, beta agonists or antiasthmaticsteroids such as prednisone and prednisolone, orally, parenterally,rectally, or by inhalation, for example in the form of an aerosol,micropulverized powder or nebulized solution. For oral administration,they can be administered in the form of tablets, capsules, for example,in admixture with talc, starch, milk sugar or other inert ingredients,that is, pharmaceutically acceptable carriers, or in the form of aqueoussolutions, suspensions, elixirs or aqueous alcoholic solutions, forexample, in admixture with sugar or other sweetening agents, flavoringagents, colorants, thickeners and other conventional pharmaceuticalexcipients. For parenteral administration, they can be administered assolutions or suspension, for example, as an aqueous or peanut oil orsuspension using excipients and carriers conventional for this mode ofadministration. For administration as aerosols, they can be dissolved ina suitable pharmaceutically acceptable solvent, for example, ethylalcohol or combinations of miscible solvents, and mixed with apharmaceutically acceptable propellant. Such aerosol compositions arepackaged for use in pressurized container fined with an aerosol valvesuitable for release of the pressurized composition. Preferably, theaerosol valve is a metered valve, that is one which on activationreleases a predetermined effective dose of the aerosol composition.

EXPERIMENTAL SECTION

The Examples which follow further illustrate the invention. Alltemperatures set forth in the specification and the Examples are indegrees Centigrade. Melting points were taken on a Thomas Hoovercapillary melting point apparatus and are uncorrected. All compoundswere characterized by proton magnetic resonance spectra taken on aVarian XL-200 or XL-400 spectrometer and electron impact or fast atombombardment (+FAB) mass spectra taken on either VG ZAB-1F or VG 70E-HFmass spectrometers. Preparative high-pressure liquid chromatography(HPLC) was performed on silica gel Prep-Pak 500 cartridges using aWaters Associates Prep LC 500A. Extracts were dried over anhydrousmagnesium sulfate unless otherwise noted.

EXAMPLE 1 3,5-Bis(decyloxy)benzoic acid methyl ester

A mixture of 25.0 g (0.149 mol) of methyl 3,5-dihydroxy benzoate, 68 ml(0.327 mol) of 1-bromodecane and 41 g (0.298 mol) of anhydrous potassiumcarbonate in 500 ml of anhydrous DMF was stirred and heated at 75° for23 hours. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure (oil pump) at 60°. The residue wasstirred with 650 ml of 0.5N HCl for 2 hours and the crude product wasremoved by filtration. Recrystallization from methanol gave 40.5 g (61%yield, mp 52°-53°) of 3,5-bis(decyloxy)benzoic acid methyl ester.

Anal. Calcd for C₂₈ H₄₈ O₄ : C, 74.95; H, 10.78. Found: C, 75.11; H,10.99.

Following the procedure of Example 1 and using 3,5-dihydroxybenzoic acidmethyl(or phenylmethyl ester) and the appropriate alkyl bromide orepoxidethe compounds in Table 1 were prepared. Following the procedureof Example 1 using 2,3-, 3,4-, 2,4-, and 2,5-dihydroxy benzoic acidmethyl esters andthe appropriate alkyl bromide the compounds in Table 1Awere prepared.

                                      TABLE 1                                     __________________________________________________________________________     ##STR21##                                                                                                Microanalytical Data                                                          Calcd Found                                       Ex.                                                                              R           R' mp (°C.)                                                                    E.F. C  H  C   H                                       __________________________________________________________________________    1a OC.sub.4 H.sub.9                                                                          CH.sub.3                                                                         liquid                                                                             C.sub.16 H.sub.24 O.sub.4                                                                *N.O.                                       1b OC.sub.6 H.sub.13                                                                         CH.sub.3                                                                         liquid                                                                             C.sub.20 H.sub.32 O.sub.4                                                                N.O.                                        1c OC.sub.8 H.sub.17                                                                         CH.sub.3                                                                         38-40                                                                              C.sub.24 H.sub.30 O.sub.4                                                                N.O.                                        1d OC.sub.12 H.sub.25                                                                        CH.sub.3                                                                         59-61                                                                              C.sub.23 H.sub.56 O.sub.4                                                                N.O.                                        1e OC.sub.14 H.sub.29                                                                        CH.sub.3                                                                         67-69                                                                              C.sub.36 H.sub.64 O.sub.4                                                                N.O.                                        1f OC.sub.18 H.sub.37                                                                        CH.sub.3                                                                         78-80                                                                              C.sub.44 H.sub.80 O.sub.4                                                          78.51                                                                            11.92                                                                            78.42                                                                             11.81                                   1g O(CH.sub.2).sub.3 C.sub.6 H.sub.5                                                         CH.sub.3                                                                         liquid                                                                             C.sub.26 H.sub.28 O.sub. 4                                                               N.O.                                        1h OCH.sub.2 CHOHC.sub.8 H.sub.17                                                            CH.sub.3                                                                         60-62                                                                              C.sub.28 H.sub.48 O.sub.6                                                          69.96                                                                            10.07                                                                            70.25                                                                             10.05                                   1i OCH.sub.2 CHOHC.sub.10 H.sub.21                                                           CH.sub.3                                                                         66-68                                                                              C.sub.32 H.sub.56 O.sub.6                                                          71.60                                                                            10.52                                                                            71.76                                                                             10.49                                   1j O(CH.sub.2).sub.4 COOCH.sub.3                                                             Bz liquid                                                                             C.sub.26 H.sub.32 O.sub.8                                                                N.O.                                        1k O(CH.sub.2).sub.10 COOCH.sub.3                                                            CH.sub.3                                                                         76-77                                                                              C.sub.32 H.sub.52 O.sub.8                                                          68.06                                                                            9.28                                                                             67.67                                                                             9.52                                    1m O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -2-C.sub.6 H.sub.5                                     CH.sub.3                                                                         77-79                                                                              C.sub.38 H.sub.36 O.sub.6                                                                N.O.                                        1n O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-C.sub.6 H.sub.5                                     CH.sub.3                                                                         liquid                                                                             C.sub.38 H.sub.36 O.sub.6                                                             N.O.                                           1o O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-C.sub.6 H.sub.5                                     CH.sub.3                                                                         145  C.sub.38 H.sub.36 O.sub.6                                                          77.53                                                                            6.16                                                                             77.48                                                                             5.83                                    1p O(CH.sub.2).sub.2 O-2-Naphthyl                                                            CH.sub.3                                                                         132-137                                                                            C.sub.32 H.sub.28 O.sub.6                                                          75.58                                                                            5.55                                                                             75.19                                                                             5.44                                    1q O(CH.sub.2).sub.2 O-1-Naphthyl                                                            CH.sub.3                                                                         116-118                                                                            C.sub.32 H.sub.28 O.sub.6                                                                    N.O.                                    __________________________________________________________________________    *Not Obtained                                                             

                                      TABLE 1A                                    __________________________________________________________________________                                   Microanalytical Data                                                          Calcd   Found                                  Structure    Ex.                                                                              R    mp(°C.)                                                                     E.F. C  H  N C   H  N                               __________________________________________________________________________     ##STR22##   1r 1s                                                                            OC.sub.10 H.sub.21 OC.sub.14 H.sub.29                                              oil oil                                                                            C.sub.28 H.sub.48 O.sub.4 C.sub.36 H.sub.64                                   O.sub.4                                                                            74.95                                                                            10.78                                                                              74.77 N.O.*                                                                       10.46                               ##STR23##   1t 1u                                                                            OC.sub.10 H.sub.21 OC.sub.14 H.sub.29                                              40-41 49-50                                                                        C.sub.28 H.sub.48 O.sub.4 C.sub.36 H.sub.64                                   O.sub.4                                                                            74.95 77.09                                                                      10.78 11.50                                                                        74.78 76.98                                                                       10.63 11.34                         ##STR24##   1v 1w                                                                            OC.sub.10 H.sub.21 OC.sub.14 H.sub.29                                              oil 33-34                                                                          C.sub.28 H.sub.48 O.sub.4 C.sub.36 H.sub.64                                   O.sub.4          N.O. N.O.                           ##STR25##   1x 1y                                                                            OC.sub.10 H.sub.21 OC.sub.14 H.sub.29                                              oil oil                                                                            C.sub.28 H.sub.48 O.sub.4 C.sub.36 H.sub.64                                   O.sub.4          N.O. N.O.                          __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 2 3,5-Bis(decyloxy)benzoic acid

A solution of 6.0 g (0.013 mol) of 3,5-bis(decyloxy)benzoic acid methylester in 300 ml of methanol and 40 ml of 1N sodium hydroxide was stirredat reflux for 3.5 hours. The reaction mixture was concentrated underreduced pressure and the residue was acidified with 6N HCl. The productwas extracted with ethyl acetate and the dried extract was concentratedunder reduced pressure to a yellow solid. Recrystallization frommethanol-water gave 5.45 g (94% yield, mp 56°-58°) of3,5-bis(decyloxy)benzoic acid.

Anal. Calcd for C₂₇ H₄₆ O₄ : C, 74.61; H, 10.67. Found: C, 74.92; H,10.83.

The compounds in Tables 2 and 2A were prepared from the ester precursorsinTables 1 and 1A, respectively, using the procedure of Example 2.

                                      TABLE 2                                     __________________________________________________________________________     ##STR26##                                                                                             Microanalytical Data                                                          Calcd Found                                          Ex.                                                                              R           mp (°C.)                                                                    E.F. C  H  C  H                                           __________________________________________________________________________    2a OC.sub.4 H.sub.9                                                                          78-79                                                                              C.sub.15 H.sub.22 O.sub.4                                                          67.75                                                                            8.33                                                                             67.57                                                                            8.29                                        2b OC.sub.6 H.sub.13                                                                         55-57                                                                              C.sub.19 H.sub.30 O.sub.4                                                          70.77                                                                            9.38                                                                             70.73                                                                            9.71                                        2c OC.sub.8 H.sub.17                                                                         54-55                                                                              C.sub.23 H.sub.38 O.sub.4                                                          72.98                                                                            10.12                                                                            72.93                                                                            10.04                                       2d OC.sub.12 H.sub.25                                                                        62-63                                                                              C.sub.31 H.sub.54 O.sub.4                                                          75.87                                                                            11.09                                                                            75.80                                                                            11.04                                       2e OC.sub.14 H.sub.29                                                                        62-64                                                                              C.sub.35 H.sub.62 O.sub.4                                                          76.87                                                                            11.43                                                                            77.15                                                                            11.71                                       2f OC.sub.18 H.sub.47                                                                        78-79                                                                              C.sub.43 H.sub.78 O.sub.4                                                          78.36                                                                            11.93                                                                            78.59                                                                            11.98                                       2g O(CH.sub.2).sub.3 C.sub.6 H.sub.5                                                         107-109                                                                            C.sub.25 H.sub.26 O.sub.4                                                          76.90                                                                            6.71                                                                             76.42                                                                            6.77                                        2h OCH.sub.2 CHOHC.sub.8 H.sub. 17                                                           103-106                                                                            C.sub.27 H.sub.46 O.sub.6                                                          69.49                                                                            9.94                                                                             69.64                                                                            9.80                                        2i OCH.sub.2 CHOHC.sub.10 H.sub.21                                                           104-106                                                                            C.sub.31 H.sub.54 O.sub.6                                                          71.23                                                                            10.41                                                                            71.20                                                                            10.33                                       2j O(CH.sub.2).sub.10 COOH                                                                   105-108                                                                            C.sub.29 H.sub.46 O.sub.8                                                          66.64                                                                            8.87                                                                             66.68                                                                            8.94                                        2k O(CH.sub.2).sub.10 CH.sub.2 OH                                                            69-72                                                                              C.sub.29 H.sub.50 O.sub.6                                                          70.41                                                                            10.19                                                                            70.10                                                                            10.11                                       2l O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -2-C.sub.6 H.sub.5                                     110-113                                                                            C.sub.37 H.sub.34 O.sub.6                                                                N.O.                                           2m O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-C.sub.6 H.sub.5                                     65-69                                                                              C.sub.37 H.sub.34 O.sub.6                                                                N.O.                                           2n O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-C.sub.6 H.sub.5                                     186-187                                                                            C.sub.37 H.sub.34 O.sub.6                                                          77.33                                                                            5.96                                                                             77.28                                                                            5.90                                        2o O(CH.sub.2).sub.2 O-2-Naphthyl                                                            205-207                                                                            C.sub.31 H.sub.26 O.sub.6                                                          75.29                                                                            5.30                                                                             74.60                                                                            5.26                                        2p O(CH.sub.2).sub.2 O-1-Naphthyl                                                            213-215                                                                            C.sub.31 H.sub.26 O.sub.6                                                          75.29                                                                            5.30                                                                             74.58                                                                            5.36                                        __________________________________________________________________________    *Not Obtained                                                             

                                      TABLE 2A                                    __________________________________________________________________________                                  Microanalytical Data                                                          Calcd Found                                                 Ex.                                                                              R    mp(°C.)                                                                     E.F. C  H  C  H                                      __________________________________________________________________________     ##STR27##  2r 2s                                                                            OC.sub.10 H.sub.21 OC.sub.14 H.sub.29                                              57-58 70-71                                                                        C.sub.27 H.sub.46 O.sub.4 C.sub.35 H.sub.62                                   O.sub.4                                                                            74.61 76.87                                                                      10.67 11.43                                                                      74.61 76.32                                                                      10.23 11.33                             ##STR28##  2t 2u                                                                            OC.sub.10 H.sub.21 OC.sub.14 H.sub.29                                              117-118 112-113                                                                    C.sub.27 H.sub.46 O.sub.4 C.sub.35 H.sub.62                                   O.sub.4                                                                            74.61 76.87                                                                      10.67 11.43                                                                      74.88 76.64                                                                      10.88 11.44                             ##STR29##  2v 2w                                                                            OC.sub.10 H.sub.21 OC.sub.14 H.sub.29                                              50-52 53-54                                                                        C.sub.27 H.sub.46 O.sub.4 C.sub.35 H.sub.62                                   O.sub.4                                                                            74.61 76.87                                                                      10.67 11.43                                                                      74.26 76.77                                                                      10.90 11.09                             ##STR30##  2x 2y                                                                            C.sub.10 H.sub.21 C.sub.14 H.sub.29                                                64-66 72-73                                                                        C.sub.27 H.sub.46 O.sub.4 C.sub.35 H.sub.62                                   O.sub.4                                                                            74.61 76.87                                                                      10.67 11.43                                                                      74.41 76.49                                                                      10.56 11.15                            __________________________________________________________________________

EXAMPLE 3 3,5-Bis(decyloxy)phenylcarbamic acid phenylmethyl ester

To a stirred, ice bath cooled solution of 5.0 g (0.0115 mol) of3,5-bis(decyloxy)benzoic acid in 100 ml of anhydrous toluene was addeddropwise 3.0 ml (0.0138 mol) of diphenylphosphoryl azide followed bydropwise addition of 1.9 ml (0.0138 mol) of triethylamine. The reactionmixture was stirred in the ice bath for 75 minutes and then was heatedat 90° for 2 hours. Benzyl alcohol (100 ml) was added and thesolutionwas stirred and heated at 90° for 3.5 hours. The solvent wasremovedunder reduced pressure and most of the excess benzyl alcohol wasremoved at80°/0.1 mm. Sodium bicarbonate solution (100 ml) was added tothe residue and the product was extracted with ethyl acetate. The driedextract was concentrated at reduced pressure to an oil which waspurified by HPLC using 25% hexane-ethyl acetate to give 4.87 g (79%yield) of 3,5-bis(decyloxy)phenylcarbamic acid phenylmethyl ester as anoil.

Anal. Calcd for C₃₄ H₅₃ NO₄ : C, 75.65; H, 9.90; N, 2.59. Found: C,75.52; H, 9.79; N, 2.68.

The compounds in Table 3 were prepared using the procedure in Example 3starting with the appropriate carboxylic acid.

                                      TABLE 3                                     __________________________________________________________________________     ##STR31##                                                                                                Microanalytical Data                                                          Calcd    Found                                    Ex.                                                                              R           R'                                                                              mp (°C.)                                                                    E.F.  C  H  N  C  H  N                                  __________________________________________________________________________    3a OC.sub.4 H.sub.9                                                                          Bz                                                                              43-45                                                                              C.sub.22 H.sub.29 NO.sub.4                                                          71.13                                                                            7.87                                                                             3.77                                                                             71.21                                                                            7.95                                                                              3.84                              3b OC.sub.6 H.sub.13                                                                         Bz                                                                              liquid                                                                             C.sub.26 H.sub.37 NO.sub.4                                                          73.04                                                                            8.72                                                                             3.28                                                                             72.63                                                                            8.92                                                                              3.35                              3c OC.sub.8 H.sub.17                                                                         Bz                                                                              liquid                                                                             C.sub.30 H.sub.45 NO.sub.4                                                          74.50                                                                            9.38                                                                             2.90                                                                             75.02                                                                            9.71                                                                              3.07                              3d OC.sub.12 H.sub.25                                                                        Bz                                                                              48-50                                                                              C.sub.38 H.sub.61 NO.sub.4                                                          76.59                                                                            10.32                                                                            2.35                                                                             76.27                                                                            10.20                                                                             2.23                              3e OC.sub.14 H.sub.29                                                                        Bz                                                                              59-61                                                                              C.sub.42 H.sub.69 NO.sub.4                                                          77.37                                                                            10.67                                                                            2.15                                                                             77.60                                                                            10.93                                                                             2.08                              3f OC.sub.18 H.sub.37                                                                        Bz                                                                              74-76                                                                              C.sub.50 H.sub.85 NO.sub.4                                                          78.58                                                                            11.21                                                                            1.83                                                                             78.66                                                                            11.01                                                                             1.75                              3g O(CH.sub.2).sub.3 C.sub.6 H.sub.5                                                         Bz                                                                              89-91                                                                              C.sub.32 H.sub.33 NO.sub.4                                                          77.55                                                                            6.71                                                                             2.83                                                                             77.15                                                                            6.67                                                                              2.70                              3h OCH.sub.2 CH(OAc)C.sub.8 H.sub.17                                                         Bz                                                                              liquid                                                                             C.sub.38 H.sub.57 NO.sub.8                                                                      N.O.                                  3i O(CH.sub.2).sub.4 COOCH.sub.3                                                             Bz                                                                              liquid                                                                             C.sub.26 H.sub.33 NO.sub.8                                                                      N.O.                                  3j O(CH.sub.2).sub.10 COOCH.sub.3                                                            Bz                                                                              liquid                                                                             C.sub.38 H.sub.57 NO.sub.8                                                                      N.O.                                  3k O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -2-C.sub.6 H.sub.5                                     Bz                                                                              84-90                                                                              C.sub.44 H.sub.41 NO.sub.8                                                                      N.O.                                  3l O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-C.sub.6 H.sub.5                                     Bz                                                                              100-106                                                                            C.sub.44 H.sub.41 NO.sub.6                                                                      N.O.                                  3m O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-C.sub.6 H.sub.5                                     Bz                                                                              125-129                                                                            C.sub.44 H.sub.41 NO.sub.6                                                          77.74                                                                            6.08                                                                             2.06                                                                             77.18                                                                            6.28                                                                              2.02                              3n O(CH.sub.2).sub.2 O-2-Naphthyl                                                            Bz                                                                              160-163                                                                            C.sub.38 H.sub.33 NO.sub.6                                                          76.11                                                                            5.55                                                                             2.34                                                                             75.59                                                                            5.61                                                                              2.26                              3o OCOC.sub.9 H.sub.19                                                                       Bz                                                                              liquid                                                                             C.sub.34 H.sub.49 NO.sub.6                                                                      N.O.                                  __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 4 3,5-bis(decyloxy)benzenamine

A mixture of 34 g (0.063 mol) of 3,5-bis(decyloxy)phenylcarbamic acidphenylmethyl ester and 4.0 g of 10% palladium on charcoal in 650 ml ofethyl acetate was shaken under a hydrogen atmosphere at room temperaturefor 4 hours. The reaction mixture was filtered to remove the catalystand the filtrate was concentrated under reduced pressure to yield 25 g(98% yield, mp 48°-50°) of 3,5-bis(decyloxy)benzenamine.

Anal. Calcd for C₂₆ H₄₇ NO₂ : C, 76.98; H, 11.68; N, 3.45. Found: C,76.82; H, 11.49; N, 3.39.

The compounds in Table 4 were prepared using the procedure of Example 4starting with the appropriate phenyl carbamic acid benzyl ester.

                                      TABLE 4                                     __________________________________________________________________________     ##STR32##                                                                                              Microanalytical Data                                                          Calcd    Found                                      Ex.                                                                              R           mp (°C.)                                                                    E.F.  C  H  N  C  H   N                                   __________________________________________________________________________    4a OC.sub.4 H.sub.9                                                                          39-41                                                                              C.sub.14 H.sub.23 NO.sub.2                                                          70.85                                                                            9.77                                                                             5.90                                                                             70.63                                                                            9.64                                                                              5.99                                4b OC.sub.6 H.sub.13                                                                         33-35                                                                              C.sub.18 H.sub.31 NO.sub.2                                                          73.67                                                                            10.65                                                                            4.77                                                                             73.60                                                                            10.61                                                                             4.92                                4c OC.sub.8 H.sub.17                                                                         41-43                                                                              C.sub.22 H.sub.39 NO.sub.2                                                          75.59                                                                            11.25                                                                            4.01                                                                             76.06                                                                            11.17                                                                             3.84                                4d OC.sub.12 H.sub.25                                                                        51-53                                                                              C.sub.30 H.sub.55 NO.sub.2                                                          78.03                                                                            12.01                                                                            3.03                                                                             77.75                                                                            11.87                                                                             3.01                                4e OC.sub.14 H.sub.29                                                                        57-58                                                                              C.sub.34 H.sub.63 NO.sub.2                                                          78.85                                                                            12.26                                                                            2.70                                                                             79.06                                                                            12.31                                                                             2.60                                4f OC.sub.18 H.sub.37                                                                        69-71                                                                              C.sub.42 H.sub.79 NO.sub.2                                                          80.06                                                                            12.64                                                                            2.22                                                                             80.26                                                                            12.95                                                                             2.36                                4g O(CH.sub.2).sub.3 C.sub.6 H.sub.5                                                         78-80                                                                              C.sub.24 H.sub.27 NO.sub.2                                                          79.74                                                                            7.53                                                                             3.87                                                                             80.87                                                                            7.71                                                                              3.90                                4h OCH.sub.2 CH(OAc)C.sub.8 H.sub.17                                                         liquid                                                                             C.sub.30 H.sub.51 NO.sub.6                                                                      N.O.                                    4i O(CH.sub.2).sub.4 COOCH.sub.3                                                             liquid                                                                             C.sub.18 H.sub.27 NO.sub.6                                                                      N.O.                                    4j O(CH.sub.2).sub.10 COOCH.sub.3                                                            57-59                                                                              C.sub.30 H.sub.51 NO.sub.6                                                          69.06                                                                            9.85                                                                             2.68                                                                             69.23                                                                            9.96                                                                              2.68                                4k O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -2-C.sub.6 H.sub.5                                     75-83                                                                              C.sub.36 H.sub.35 NO.sub.4                                                                      N.O.                                    4l O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-C.sub.6 H.sub.5                                     40-45                                                                              C.sub.36 H.sub.35 NO.sub.4                                                          79.24                                                                            6.47                                                                             2.57                                                                             78.82                                                                            6.52                                                                              2.57                                4m O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-C.sub.6 H.sub.5                                     149-150                                                                            C.sub.36 H.sub.45 NO.sub.4                                                          79.24                                                                            6.47                                                                             2.57                                                                             78.54                                                                            6.51                                                                              2.50                                4n O(CH.sub.2).sub.2 O-2-Naphthyl                                                            177-181                                                                            C.sub.30 H.sub.27 NO.sub.4                                                                      N.O.                                    4o O(CH.sub.2).sub.2 O-1-Naphthyl                                                            175-178                                                                            C.sub.30 H.sub.27 NO.sub.4                                                                      N.O.                                    4p OCOC.sub.9 H.sub.19                                                                       43-44                                                                              C.sub. 26 H.sub.43 NO.sub.4                                                         72.02                                                                            10.00                                                                            3.23                                                                             71.78                                                                            9.82                                                                              3.31                                __________________________________________________________________________

EXAMPLE 5 N-(2-Methoxy-2-oxoethyl)-N-[3,5-bis(decyloxy)phenyl]glycinemethyl ester

A mixture of 2.0 g (4.93 mmol) of 3,5-bis(decyloxy)benzenamine, 1.4 ml(14.8 mmol) of methyl bromoacetate, 2.65 g (12.3 mmol) of1,8-bis(dimethylamino)naphthalene (Proton sponge) and 0.21 g (1.38 mmol)of sodium iodide in 50 ml of anhydrous acetonitrile and 15 ml ofanhydrousDMF was stirred at reflux under an argon atmosphere for 27hours. The reaction mixture was concentrated under reduced pressure andthe residue was extracted with ethyl acetate. The extract was washedwith 0.5N HCl, dried and concentrated under reduced pressure to an oilwhich was purifiedby HPLC using 15% ethyl acetate-hexane to give 1.2 g(44% yield, mp 36°-38°) ofN-(2-methoxy-2-oxoethyl)-N-[3,5-bis(decyloxy)phenyl]glycine methylester.

Anal. Calcd for C₃₂ H₅₅ NO₆ : C, 69.91; H, 10.08; N, 2.55. Found: C,69.59; H, 10.10; N, 2.38.

The compounds in Table 5 were prepared using the procedure of Example 5starting with the appropriate amine and bromo ester.

                                      TABLE 5                                     __________________________________________________________________________     ##STR33##                                                                                                  Microanalytical Data                                                          Calcd    Found                                  Ex.                                                                              R           R' mp (°C.)                                                                    E.F.   C  H  N  C  H   N                               __________________________________________________________________________    5a OC.sub.4 H.sub.9                                                                          CH.sub.3                                                                         liquid                                                                             C.sub.20 H.sub.31 NO.sub.6                                                           62.97                                                                            8.19                                                                             3.67                                                                             62.65                                                                            8.19                                                                              3.71                            5b OC.sub.6 H.sub.13                                                                         CH.sub.3                                                                         liquid                                                                             C.sub.24 H.sub.39 NO.sub.6                                                           65.98                                                                            8.98                                                                             3.20                                                                             65.76                                                                            8.97                                                                              3.22                            5c OC.sub.8 H.sub.17                                                                         CH.sub.3                                                                         liquid                                                                             C.sub.28 H.sub.47 NO.sub.6                                                           68.12                                                                            9.60                                                                             2.84                                                                             68.13                                                                            9.73                                                                              2.86                            5d OC.sub.12 H.sub.25                                                                        CH.sub.3                                                                         43-44                                                                              C.sub.36 H.sub.63 NO.sub.6                                                           71.36                                                                            10.48                                                                            2.31                                                                             71.40                                                                            10.60                                                                             2.46                            5e OC.sub.14 H.sub.29                                                                        Bz 58-62                                                                              C.sub.52 H.sub.79 NO.sub.6                                                           76.71                                                                            9.79                                                                             1.72                                                                             76.68                                                                            9.98                                                                              1.66                            5f OC.sub.18 H.sub.37                                                                        Bz 64-66                                                                              C.sub.60 H.sub.95 NO.sub.6                                                           77.79                                                                            10.34                                                                            1.51                                                                             77.57                                                                            10.06                                                                             1.52                            5g O(CH.sub.2).sub.3 C.sub.6 H.sub.5                                                         Bz liquid                                                                             C.sub.42 H.sub.43 NO.sub.6                                                                       N.O.                                5h OCH.sub.2 CH(OAc)C.sub.8 H.sub.17                                                         CH.sub.3                                                                         liquid                                                                             C.sub.36 H.sub.59 NO.sub.10                                                          64.94                                                                            8.93                                                                             2.10                                                                             65.09                                                                            8.90                                                                              1.98                            5i O(CH.sub.2).sub.4 COOCH.sub.3                                                             CH.sub.3                                                                         liquid                                                                             C.sub.24 H.sub.35 NO.sub.10                                                          57.94                                                                            7 09                                                                             2.82                                                                             57.73                                                                            6.95                                                                              2.81                            5j O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -2-C.sub.6 H.sub.5                                     Bz liquid                                                                             C.sub.54 H.sub.51 NO.sub.8                                                                       N.O.                                5k O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-C.sub.6 H.sub.5                                     Bz liquid                                                                             C.sub.54 H.sub.51 NO.sub.8                                                                       N.O.                                5l O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-C.sub.6 H.sub.5                                     Bz 94-96                                                                              C.sub.54 H.sub.51 NO.sub.8                                                           77.03                                                                            6.11                                                                             1.66                                                                             76.60                                                                            6.14                                                                              1.70                            5m O(CH.sub.2).sub.2 O-2-Naphthyl                                                            Bz 120-125                                                                            C.sub.48 H.sub.43 NO.sub.8                                                           75.67                                                                            5.69                                                                             1.84                                                                             75.55                                                                            5.79                                                                              1.74                            5n O(CH.sub.2).sub.2 O-1-Naphthyl                                                            Bz 150-153                                                                            C.sub.48 H.sub.43 NO.sub.8                                                           75.67                                                                            5.69                                                                             1.84                                                                             75.23                                                                            5.69                                                                              1.66                            5o CONHC.sub.14 H.sub.29                                                                     Bz 110-111                                                                            C.sub.54 H.sub.81 N.sub.3 O.sub.6                                                    74.40                                                                            9.40                                                                             4.84                                                                             74.77                                                                            9.31                                                                              4.82                            5p CONHC.sub.18 H.sub.37                                                                     Bz 105-110                                                                            C.sub.62 H.sub.97 N.sub.3 O.sub.6                                                    75.95                                                                            9.97                                                                             4.29                                                                             76.15                                                                            10.14                                                                             4.36                            5q CONH-1-Adamantyl                                                                          Bz 169-171                                                                            C.sub.46 H.sub.53 N.sub.3 O.sub.6                                                    74.27                                                                            7.19                                                                             5.65                                                                             74.07                                                                            7.15                                                                              5.62                            5r C.sub.19 H.sub.49                                                                         Bz 50-51                                                                              C.sub.62 H.sub.99 NO.sub.4                                                           80.72                                                                            10.82                                                                            1.52                                                                             80.54                                                                            10.59                                                                             1.51                            5s OCOC.sub.9 H.sub.19                                                                       Bz liquid                                                                             C.sub.44 H.sub.59 NO.sub.8                                                                       N.O.                                5t COOC.sub.10 H.sub.21                                                                      Bz liquid                                                                             C.sub.46 H.sub.63 NO.sub.8                                                                       N.O.                                __________________________________________________________________________

EXAMPLE 6 N-(Carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine

A solution of 0.205 g (0.373 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3,5-bis(decyloxy) phenyl]glycine methylester and 1.5 ml (1.5 mmol) of 1.0N NaOH in 10 ml of methanol wasstirred at reflux for 30 minutes. The solvent was removed under reducedpressure and the residue was acidified with 0.18 ml of acetic acid theproduct was extracted with ethyl acetate and the dried extract wasconcentrated at reduced pressure to a solid. Recrystallization frommethanol-water gave 61mg (mp 110°-114°) ofN-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine.

Anal. Calcd for C₃₀ H₅₁ NO₆ : C, 69.06; H, 9.85; N, 2.68. Found: C,69.09; H, 9.93: N, 2.57

The compounds in Table 6 were prepared using the procedure of Example 6formethyl ester starting materials and using the procedure of Example 8for benzyl ester starting materials.

                                      TABLE 6                                     __________________________________________________________________________     ##STR34##                                                                                               Microanalytical Data                                                          Calcd    Found                                     Ex.                                                                              R           mp (°C.)                                                                    E.F.   C  H  N  C  H  N                                   __________________________________________________________________________    6a OC.sub.4 H.sub.9                                                                          147-149                                                                            C.sub.18 H.sub.27 NO.sub.6                                                           61.17                                                                            7.70                                                                             3.96                                                                             61.12                                                                            7.60                                                                             3.97                                6b OC.sub.6 H.sub.13                                                                         120-122                                                                            C.sub.22 H.sub.35 NO.sub.6                                                           64.52                                                                            8.61                                                                             3.42                                                                             64.42                                                                            8.81                                                                             3.56                                6c OC.sub.8 H.sub.17                                                                         119-123                                                                            C.sub.26 H.sub.43 NO.sub.6                                                           67.07                                                                            9.31                                                                             3.01                                                                             67.11                                                                            9.51                                                                             2.90                                6d OC.sub.12 H.sub.25                                                                        106-109                                                                            C.sub.34 H.sub.59 NO.sub.6                                                           70.67                                                                            10.29                                                                            2.42                                                                             70.57                                                                            10.46                                                                            2.35                                6e OC.sub.14 H.sub.29                                                                        103-106                                                                            C.sub.38 H.sub.67 NO.sub.6                                                           72.00                                                                            10.65                                                                            2.21                                                                             72.01                                                                            10.54                                                                            2.13                                6f OC.sub.18 H.sub.37                                                                        85-89                                                                              C.sub.46 H.sub.83 NO.sub.6                                                           74.05                                                                            11.21                                                                            1.89                                                                             73.58                                                                            11.07                                                                            1.82                                6g O(CH.sub.2).sub.3 C.sub.6 H.sub.5                                                         150-153                                                                            C.sub.28 H.sub.31 NO.sub.6                                                           70.42                                                                            6.54                                                                             2.93                                                                             70.54                                                                            6.64                                                                             2.85                                6h OCH.sub.2 CHOHC.sub.8 H.sub.17                                                            121-125                                                                            C.sub.30 H.sub.51 NO.sub.8                                                           65.07                                                                            9.28                                                                             2.53                                                                             65.12                                                                            9.15                                                                             2.54                                6i O(CH.sub.2).sub.4 COOH                                                                    172-174                                                                            C.sub.20 H.sub.27 NO.sub.10                                                          54.42                                                                            6.17                                                                             3.17                                                                             54.56                                                                            6.23                                                                             3.20                                6j O(CH.sub.2).sub.10 COOCH.sub.3                                                            74-76                                                                              C.sub.34 H.sub.55 NO.sub.10                                                          64.03                                                                            8.69                                                                             2.20                                                                             63.89                                                                            8.75                                                                             2.07                                6k O(CH.sub.2).sub.10 COOH                                                                   146-147                                                                            C.sub.32 H.sub.51 NO.sub.10                                                          63.03                                                                            8.43                                                                             2.30                                                                             62.69                                                                            8.40                                                                             2.32                                6l O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -2-C.sub.6 H.sub.5                                     100-112                                                                            C.sub.40 H.sub.39 NO.sub.8                                                           72.60                                                                            5.94                                                                             2.12                                                                             72.34                                                                            5.95                                                                             2.05                                6m O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-C.sub.6 H.sub.5                                     foam C.sub.40 H.sub.39 NO.sub.8                                                           72.60                                                                            5.94                                                                             2.12                                                                             71.84                                                                            5.77                                                                             1.93                                6n O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-C.sub.6 H.sub.5                                     155-159                                                                            C.sub.40 H.sub.39 NO.sub.8                                                           72.60                                                                            5.94                                                                             2.12                                                                             72.17                                                                            5.97                                                                             2.08                                6o O(CH.sub.2).sub.2 O-2-Naphthyl                                                            185-192                                                                            C.sub.40 H.sub.31 NO.sub.8                                                           70.21                                                                            5.37                                                                             2.41                                                                             68.40                                                                            5.19                                                                             2.40                                6p O(CH.sub.2).sub.2 O-1-Naphthyl                                                            169-170                                                                            C.sub.34 H.sub.31 NO.sub.8                                                           70.21                                                                            5.37                                                                             2.41                                                                             69.53                                                                            5.68                                                                             2.31                                6q CONHC.sub.14 H.sub.29                                                                     169-176                                                                            C.sub.40 H.sub.69 N.sub.3 O.sub.6                                                    69.83                                                                            10.11                                                                            6.11                                                                             70.01                                                                            10.06                                                                            6.07                                6r CONHC.sub.18 H.sub.37                                                                     175-181                                                                            C.sub.48 H.sub.85 N.sub.3 O.sub.6                                                    72.05                                                                            10.71                                                                            5.25                                                                             72.14                                                                            11.04                                                                            5.24                                6s CONH-1-Adamantyl                                                                          285-290                                                                            C.sub.32 H.sub.41 N.sub.3 O.sub.6                                                    68.18                                                                            7.33                                                                             7.45                                                                             68.09                                                                            7.30                                                                             7.43                                6t C.sub.19 H.sub.39                                                                         88-92                                                                              C.sub.48 H.sub.87 NO.sub.4                                                           77.67                                                                            11.82                                                                            1.89                                                                             77.40                                                                            11.89                                                                            2.14                                6u OCOC.sub.9 H.sub.19                                                                       140-145                                                                            C.sub.30 H.sub.47 NO.sub.8                                                           65.55                                                                            8.62                                                                             2.55                                                                             65.27                                                                            8.73                                                                             2.68                                6v COOC.sub.10 H.sub.21                                                                      100-102                                                                            C.sub.32 H.sub.51 NO.sub.8                                                           66.52                                                                            8.90                                                                             2.42                                                                             66.51                                                                            8.99                                                                             2.50                                __________________________________________________________________________

EXAMPLE 7N-[3,5-bis(Decyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester

A mixture of 20.0 g (0.0493 mol) of 3,5-bis(decyloxy)benzenamine, 23.6ml (0.148 mol) of benzyl bromoacetate, 26.4 g (0.123 mol) of1,8-bis(dimethylamino)naphthalene and 2.1 g of sodium iodide in 300 mlacetonitrile and 65 ml of DMF was stirred at reflux for 48 hours. Thereaction mixture was concentrated under reduced pressure and the residuewas extracted with ethyl acetate. The extract was washed with 0.5N HCl,with saturated NaHCO₃, dried and concentrated under reduced pressure toan oil. Purification by HPLC using 10% ethyl acetate-hexane gave 15.7g(45% yield, mp 55°-57°) ofN-[3,5-bis(decyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester.

Anal. Calcd for C₄₄ H₆₃ NO₆ : C,75.28; H, 9.04; N, 2.00. Found: C,75.49; H, 9.14; N, 2.10.

EXAMPLE 8 N-(Carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine

A mixture of 10.2 g (0.0145 mol) ofN-[3,5-bis(decyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester and 1.5 g of 10% palladium on charcoal in 500 ml ofTHFwas shaken in a hydrogen atmosphere at room temperature for 7 hours.The catalyst was removed by filtration and the filtrate was concentratedunderreduced pressure to a solid which was recrystallized fromacetonitrile to give 5.66 g (75% yield, mp 110°-114°) ofN-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine.

EXAMPLE 9 N,N'-Didecyl-5-nitro-1,3-benzenedicarboxamide

To 30 g (0.14 mol) of 5-nitroisophthalic acid suspended in 120 ml ofthionyl chloride was added 2 ml of DMF and the solution was stirred atreflux for 3.5 hours. The excess thionyl chloride was removed at reducedpressure and the residual acid chloride was dissolved in 220 ml ofanhydrous tetrahydrofuran. This solution was added dropwise to 64 ml(0.32mol) of decyl amine and 44 ml (0.32 mol) of triethylamine in 350 mlof anhydrous tetrahydrofuran over 30 minutes with ice bath cooling. Thereaction mixture was stirred at room temperature for 4 hours and thenpoured into 3 L of water. The resultant solid was removed by filtrationand recrystallized from methanol to give 51.5 g (74% yield, mp115°-116°) of N,N'-didecyl-5-nitro-1,3-benzenedicarboxamide.

Anal. Calcd for C₂₈ H₄₇ N₃ O₄ : C, 68.68; H, 9.67; N, 8.58. Found:C,68.45; H ,9.56; N, 8.67.

The compounds in Table 7 were prepared by the procedure of Example 9.

                                      TABLE 7                                     __________________________________________________________________________     ##STR35##                                                                                              Microanalytical Data                                                          Calcd    Found                                      Ex.                                                                              R          mp (°C.)                                                                    E.F.   C  H  N  C  H  N                                    __________________________________________________________________________    9a CONHC.sub.14 H.sub.29                                                                    110-114                                                                            C.sub.36 H.sub.63 N.sub.3 O.sub.4                                                    71.84                                                                            10.55                                                                            6.98                                                                             72.15                                                                            10.70                                                                            6.93                                 9b CONHC.sub.18 H.sub.47                                                                    100-110                                                                            C.sub.44 H.sub.79 N.sub.3 O.sub.4                                                    74.00                                                                            11.15                                                                            5.88                                                                             73.98                                                                            11.01                                                                            5.80                                 9c CONH-1-Adamantyl                                                                         >350 C.sub.28 H.sub.35 N.sub.3 O.sub.4                                                    70.42                                                                            7.39                                                                             8.80                                                                             70.20                                                                            7.51                                                                             8.95                                 __________________________________________________________________________

EXAMPLE 10 5-Amino-N,N'-didecyl-1,3-benzenedicarboxamide

A mixture of 21 g (0.043 mol) ofN,N'-didecyl-5-nitro-1,3-benzenedicarboxamide and 7.0 g of 10% palladiumon carbon in 250 ml of tetrahydrofuran was shaken under hydrogenpressure (52 psi initially) on a Parr Hydrogenator for 17 hours. Thecatalyst was removed by filtration and the solvent was removed from thefiltrate at reduced pressure to give a solid which was recrystallizedfrom methanol-water to give 15.3 g (77% yield, mp 188°-189°) of5-amino-N,N'-didecyl-1,3-benzenedicarboxamide.

Anal. Calcd for C₂₈ H₄₉ N₃ O₂ : C, 73.16; H, 10.74; N, 9.14. Found: C,72.93; H, 10.70; N, 8.90.

Using the procedure of Example 10, hydrogenation ofN,N'-ditetradecyl-5-nitro-1,3-benzenedicarboxamide gave5-amino-N,N'-ditetradecyl-1,3-benzenedicarboxamide, mp 171°-178°.

Using the procedure of Example 10, hydrogenation of5-nitro-N,N'-bis(tricyclo[3.3.1.1./3,7/]dec-1-yl)-1,3-benzenedicarboxamidegave5-amino-N,N'-bis(tricyclo[3.3.1.1./3,7]dec-1-yl)-1,3-benzenedicarboxamide(mp>300°, Anal. Calcd for C₂₈ H₃₇ N₃ O₂ : C, 75.13; H, 8.33; N, 9.39.Found: C, 74.88; H, 8.25; N, 9.47.

EXAMPLE 11 N-[3,5-Bis[(decylamino)carbonyl]phenyl]glycine methyl ester

A mixture of 0.202 g (0.455 mmol) of5-amino-N,N'-didecyl-1,3-benzenedicarboxamide, 0.17 ml (1.8 mmol) ofmethyl bromoacetate, 0.14 g (1 mmol) of potassium carbonate and 0.15 g(1 mmol) of sodium iodide in 10 ml of acetone and 2 ml of DMF wasstirred at reflux for 20 hours. Water was added and the product wasextracted with ethyl acetate. The dried extract was concentrated atreduced pressure to an oil which was crystallized from methanol-water togive 0.1608 g (67% yield, mp 108°-109°) ofN-[3,5-bis[(decylamino)carbonyl]phenyl]glycine methyl ester.

Anal. Calcd for C₃₁ H₅₃ N₃ O₄ : C, 70.02; H, 10.05; N, 7.90. Found: C,69.74; H, 10.21; N, 7.73.

EXAMPLE 12 N-[3,5-Bis[(decylamino)carbonyl]phenyl]glycine

A solution of 0.103 g (0.19 mmol) ofN-[3,5-bis(decylamino)carbonyl]phenyl]glycine methyl ester and 0.4 ml(0.4mmol) of 1.0N NaOH was kept at room temperature for 18 hours. Water(30 ml)was added and the pH was adjusted to 4 by the addition of aceticacid. The resultant solid was filtered and recrystallized frommethanol-water to give 0.079 g (81% yield, mp 172°-173°) ofN-[3,5-bis[(decylamino)carbonyl]phenyl glycine.

Anal. Calcd for C₃₀ H₅₁ N₃ O₄ : C, 69.60; H, 9.93; N, 8.12. Found: C,69.29; H, 9.95; N, 8.11.

EXAMPLE 13 N-[3,5-Bis[(decylamino)carbonyl]phenyl]glycine phenylmethylester

A mixture of 7.0 g (15.2 mmol) of5-amino-N,N'-didecyl-1,3-benzenedicarboxamide, 9.7 ml ofbenzylbromoacetate, 4.6 g (30.4 mmol) of sodium iodide and 4.2 g (30.4mmol) of potassium carbonate in 150 ml of acetone and 50 ml of DMF wasstirred at reflux for 26 hours. The reaction mixture was filtered andthe solvents were removed from the filtrate at reduced pressure. Theresidue was purified by HPLC using 35% ethyl acetate-hexane. The purefractions were combined and recrystallized from methylene chloride-etherto give 4.3g (47% yield, mp 102°-104°) ofN-[3,5-bis[decylamino)carbonyl]phenyl]glycine phenylmethyl ester. Thenmr spectrum was consistent with the structure.

EXAMPLE 14 N-[3,5-bis[(decylamino)carbonyl]phenyl]glycine from thephenylmethyl ester

A mixture of 4.29 g (7.05 mmol) ofN-[3,5-bis[(decylamino)carbonyl]phenyl]glycine phenylmethyl ester and0.5 g of 10% palladium on carbon in 125 ml of tetrahydrofuran was shakenin a hydrogen atmosphere at room temperature for 16 hours. The catalystwas removed by filtration and the filtrate was concentrated at reducedpressure. The residue was triturated with ether and filtered to give3.31 g (91% yield, mp 168°-171°) of N-[3,5-bis(decylamino)carbonyl]phenyl]glycine.

EXAMPLE 15N-[3,5-Bis[(decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester

A mixture of 10.0 g (0.022 mol) of5-amino-N,N'-didecyl-1,3-benzenedicarboxamide, 31 ml (0.33 mol) ofmethyl bromoacetate, 6.6 g (0.044 mol) of sodium iodide, 6.1 g (0.044mol) of potassium carbonate and 0.32 g (0.001 mol) of tetrabutylammoniumbromide in 100 ml of DMF was stirred and heated at 100° for 67 hours.The reaction mixture was concentrated on the oil pump and 100 ml ofsaturated NaHCO₃ solution was added to the residue. The product wasextracted with ethyl acetate and the extract was washed with 10% sodiumbisulfite solution. The dried extract was concentrated at reducedpressure to an oilwhich was purified by HPLC using 35% ethylacetate-toluene. The combined pure fractions were crystallized frommethanol-water to give 8.2 g (63% yield, mp 71°-75°) ofN-[3,5-bis[decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester.

Anal. Calcd for C₃₄ H₅₇ N₃ O₆ : C, 67.63; H, 9.51; N, 6.96. Found: C,67.42; H, 9.81; N, 6.88.

EXAMPLE 16N-(Carboxymethyl)-N-[3,5-bis[(decylamino)carbonyl]phenyl]glycine

A solution of 8.2 g (0.0136 mol) ofN-[3,5-bis[decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester and 54 ml (0.054 mol) of 1.0N NaOH in 425 ml of methanolwas left at room temperature for 22 hours. The residue was dissolved in250 mlof water and the pH was adjusted to 3.0 with 1N HCl. The resultantsolid was removed by filtration and recrystallized from methanol-waterto give 2.96 g (38% yield, mp 164°-167°) ofN-(carboxymethyl)-N-[3,5-bis[(decylamino)carbonyl]phenyl]glycine.

Anal. Calcd for C₃₂ H₅₃ N₃ O₆ : C, 66.75; H, 9.28; N, 7.30. Found: C,66.35; H, 9.20; N, 7.04.

EXAMPLE 17 3,5-bis[(1-Oxodecyl)amino]benzoic acid

To a mixture of 5 g (0.033 mol) of 3,5-diaminobenzoic acid in 100 ml ofmethylene chloride, 50 ml of THF and 18 ml (0.13 mol) of triethylaminestirred at room temperature was added 17 ml (0.08 mol) of decanoylchloride dropwise over 10 minutes. The reaction mixture was stirred for18hours, filtered and the filtrate was concentrated at reduced pressure.Water was added to the residue and the product was extracted with ethylacetate. The dried extract was concentrated at reduced pressure and thesolid residue was recrystallized twice from methanol-water to give 8.6 g(57% yield, mp 208°-209°) of 3,5-bis[(1-oxodecyl)amino]benzoic acid.

Anal. Calcd for C₂₇ H₄₄ N₂ O₄ : C, 70.40; H, 9.63; N, 6.08. Found: C,70.32; H, 9.60; N, 6.08.

The compounds in Table 8 were prepared using the procedure of Example 17starting from the appropriate dihydroxybenzoic acid or diaminobenzoicacid.

                                      TABLE 8                                     __________________________________________________________________________     ##STR36##                                                                                        Microanalytical Data                                                          Calcd        Found                                        Ex.                                                                              R        mp (°C.)                                                                    E.F.   C  H  N  C  H  N                                      __________________________________________________________________________    17a                                                                              OCOC.sub.9 H.sub.19                                                                    50-52                                                                              C.sub.27 H.sub.42 O.sub.6                                                            70.10                                                                            9.15  70.05                                                                            9.08                                      17b                                                                              NHCOC.sub.11 H.sub.23                                                                  198-201                                                                            C.sub.31 H.sub.52 N.sub.2 O.sub.4                                                    72.05                                                                            10.14                                                                            5.42                                                                             71.93                                                                            10.10                                                                            5.32                                   17c                                                                              NHCOC.sub.13 H.sub.27                                                                  188-191                                                                            C.sub.35 H.sub.60 N.sub.2 O.sub.4                                                    73.38                                                                            10.56                                                                            4.89                                                                             73.12                                                                            10.57                                                                            4.83                                   17d                                                                              NHCOC.sub.15 H.sub.31                                                                  185-188                                                                            C.sub.39 H.sub.68 N.sub.2 O.sub.4                                                    74.47                                                                            10.90                                                                            4.45                                                                             74.50                                                                            10.88                                                                            4.53                                   17e                                                                              OCONHC.sub.8 H.sub.17                                                                  186-187                                                                            C.sub.25 H.sub.40 N.sub.2 O.sub.6                                                    64.63                                                                            8.68                                                                             6.03                                                                             64.64                                                                            8.54                                                                             6.15                                   17f                                                                              NHCONHC.sub.17 H.sub.35                                                                250-280                                                                            C.sub.43 H.sub.78 N.sub.4 O.sub.4                                                    72.22                                                                            10.99                                                                            7.83                                                                             71.50                                                                            11.16                                                                            7.69                                   17g                                                                              NHCONHC.sub.8 H.sub.17                                                                 229-231                                                                            C.sub.25 H.sub.42 N.sub.4 O.sub.4                                                    64.91                                                                            9.15                                                                             12.11                                                                            63.84                                                                            9.15                                                                             11.81                                  __________________________________________________________________________

EXAMPLE 18 [3,5-bis[(1-Oxodecyl)amino]phenyl]carbamic acid phenylmethylester

To a suspension of 5.0 g (10.85 mmol) of3,5-bis[(1-oxodecyl)amino]benzoic acid in 150 ml of anhydrous toluenecooled in an ice bath and stirred under an argon atmosphere was added2.8 ml (13.0 mmol) of diphenylphosphoryl azide followed by 1.8 ml (13.0mmol) of triethylamine. The reaction mixture was stirred in the ice bathfor 1.5 hours, at room temperature for 1 hour and then at 90° for 2hours. Benzyl alcohol (39 ml, 0.38 mol) was added and heating at 90° wascontinued for 4 hours. The solvent was removed at reduced pressure andmost of the excess benzyl alcohol was removed at 80°/1 mm. NaHCO₃solution was added and the product was extracted with ethyl acetate. Thedried extract was concentrated at reduced pressure and the residue waspurified by HPLC using 25% ethyl acetate-hexane to give 2.78 g (45%yield) of [3,5-bis[(1 -oxodecyl)amino]phenyl]carbamic acid phenylmethylester as a yellow foam. The nmr and mass spectra were compatible withthe structure.

EXAMPLE 19 N,N'-(5-Amino-1,3-phenylene)bisdecanamide

A mixture of 2.77 g (4.9 mmol) of[3,5-bis[(1-oxodecyl)amino]phenyl]carbamic acid phenylmethyl ester and0.6g of 10% palladium on carbon in 60 ml of THF was shaken under ahydrogen atmosphere at room temperature and pressure for 8 hours. Thecatalyst was removed by filtration and the filtrate was concentrated atreduced pressure. The resultant solid was triturated with ether andfiltered to give 1.94 g (92% yield, mp 152°-154°) ofN,N'-(5-amino-1,3-phenylene) bisdecanamide.

Anal. Calcd for C₂₆ H₄₅ N₃ O₂ : C, 72.34; H, 10.51; N, 9.73. Found: C,72.02; H, 10.29; N, 9.56.

EXAMPLE 20N-[3,5-bis[(1-Oxodecyl)amino]phenyl]-N-[2-oxo-2-phenylmethoxy)ethyl]glycinephenylmethylester

A mixture of 1.92 g (4.45 mmol) ofN,N'-(5-amino-1,3-phenylene)bisdecanamide, 10.6 ml (0.061 mol) of benzylbromoacetate, 2.4 g (11.1 mmol) of 1,8-bis(dimethylamino)-naphthaleneand 0.19 g (1.25 mmol) of sodium iodide in 50 ml of acetonitrile and 15ml of DMF was stirred and refluxed under an argon atmosphere for 36hours. The solvents were removed at reduced pressure and the residue wasdissolved inethyl acetate. The extract was washed with 0.05N HCl, withNaHCO₃ solution, dried and concentrated to a brown solid. Purificationby HPLC using 25% ethyl acetate-hexane gave 0.9 g which wasrecrystallized from acetone-hexane to give 0.64 g (20% yield, mp127°-129°) ofN-[3,5-bis[(1-oxodecyl)amino]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester.

Anal. Calcd for C₄₄ H₆₁ N₃ O₆ : C, 72.60; H, 8.45; N, 5.7. Found: C,72.28; H, 8.52; N, 5.71.

EXAMPLE 21 N-(Carboxymethyl)-N-3,5-bis[(1-oxodecyl)amino]phenyl]glycine

A mixture of 0.625 g (0.86 mmol) ofN-[3,5-bis[(1-oxodecyl)amino]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester and 0.2 g of 10% palladium on carbon in 25 ml of THFwas stirred in a hydrogen atmosphere at room temperature for 5 hours.The catalyst was removed by filtration and the filtrate was concentratedat reduced pressure to a solid which was recrystallized frommethanol-water to give 0.29 g (62% yield, mp 100°-102°) ofN-(carboxymethyl)-N-3,5-bis[(1-oxodecyl)amino]glycine.

Anal. Calcd for C₃₀ H₄₉ N₃ O₆ : C, 65.79; H, 9.02; N, 7.67. Found: C,65.21; H, 8.86; N, 7.58.

EXAMPLE 22 5-Nitro-1,3-benzenedicarboxylic acid ditetradecyl ester

A mixture of 1.0 g (4.7 mmol) of 5-nitroisophthalic acid, 3.1 ml (10.3mmol) of 1-bromotetradecane and 2.0 g (15 mmol) of potassium carbonatein 40 ml of anhydrous DMF was stirred and heated at 100° for 20hours.Water was added to the cooled reaction mixture and the resultantsolid was filtered and recrystallized from methylene chloride-methanolto give 2.1 g(74% yield, mp 60°-61°) of 5-nitro-1,3-benzenedicarboxylicacid ditetradecyl ester.

Anal Calcd for C₃₆ H₆₁ NO₆ : C, 71.60; H, 10.18; N, 2.32. Found: C,71.68; H, 10.26; N, 2.34.

Using this procedure the reaction of 5-nitroisophthalic acid with1-bromodecane gave 5-nitro-1,3-benzenedicarboxylic acid didecyl ester(mp 48°-50°, Anal. Calcd for C₂₈ H₄₅ NO₆ : C, 68.40; H, 9.23; N, 2.85.Found: C, 67.68; H, 9.13; N, 2.86.

EXAMPLE 23 5-Amino-1,3-benzenedicarboxylic acid ditetradecyl ester

A mixture of 2.09 g of 5-nitro-1,3-benzenedicarboxylic acid ditetradecylester and 0.5 g of 10% palladium on carbon in 80 ml of ethyl acetate and25 ml of THF was shaken under an initial hydrogen pressure of 53 psi for17 hours. The catalyst was removed by filtration and the filtrate wasconcentrated to give 1.96 g of pure 5-amino-1,3-benzenedicarboxylic acidditetradecyl ester, mp 74°-75°.

Anal. Calcd for C₃₆ H₆₃ NO₄ : C, 75.34; H, 11.06; N, 2.44. Found: C,75.49; H, 11.23; N, 2.49.

Using this procedure, the hydrogenation of5-nitro-1,3-benzenedicarboxylic acid didecyl ester gave5-amino-1,3-benzenedicarboxylic acid didecyl ester(mp 72°-73°, Anal.Calcd for C₂₈ H₄₇ NO₄ : C, 72.84; H, 10.26; N, 3.03. Found: C, 73.09; H,10.26; N, 2.99.

EXAMPLE 24N-[3,5-bis[(tetradecyloxy)carbonyl]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester and N-[[3,5-bis(tetradecyloxy)carbonyl]phenyl]glycinephenylmethyl ester

A mixture of 1.96 g (3.4 mmol) of 5-amino-1,3-benzenedicarboxylic acidditetradecyl ester, 5.4 ml (34 mmol) of benzyl bromoacetate, 1.8 g (8.5mmol) of 1,8-bis(dimethylamino) naphthalene and 0.2 g (1.36 mmol) ofsodium iodide in 40 ml of acetonitrile and 20 ml of DMF was stirred atreflux for 48 hours. The solvents were removed at reduced pressure andtheresidue was dissolved in ethyl acetate. The extract was washed with0.05N HCl twice, with NaHCO₃ solution, dried and concentrated. Theresidue was purified by chromatography on silica get using 10% ethylacetate-hexane to give 0.14 g ofN-[[3,5-bis(tetradecyloxy)carbonyl]phenyl]glycine phenylmethyl ester and0.43 g, mp 57°-58°, ofN-[3,5-bis[(tetradecyloxy)carbonyl]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester.

Anal. Calcd for C₅₄ H₇₉ NO₈ : C, 74.53; H, 9.15; N, 1.61. Found: C,74.50; H, 9.22; N, 1.63.

EXAMPLE 25N-(Carboxymethyl)-N-[3,5-bis[(tetradecyloxy)carbonyl]phenyl]glycine

A mixture of 0.43 g ofN-[3,5-bis[(tetradecyloxy)carbonyl]phenyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycinephenylmethyl ester and 0.2 g of 10% palladium on carbon in 30 ml ofethyl acetate and 20 ml of THF was shaken under an initial hydrogenpressure of 51 psi for 2 hours. The catalyst was removed by filtrationandthe filtrate was concentrated at reduced pressure to a solid whichwas recrystallized from methanol-water to give 0.28 g (82% yield, mp84°-87°) ofN-(carboxy-methyl)-N-[3,5-bis[(tetradecyloxy)carbonyl]phenyl]glycine.

Anal. Calcd for C₄₀ H₆₇ NO₈ : C, 69.63; H, 9.79; N, 2.03. Found: C,69.65; H, 9.81; N, 1.98.

EXAMPLE 26 N-[[3,5-bis-(Tetradecyloxy)carbonyl]phenyl]glycine

A mixture of 0.14 g of N-[[3,5-bis-(tetradecyloxy)carbonyl]phenylglycinephenylmethyl ester and 0.2 g of 10% palladium on carbon in 15 ml ofethyl acetate and 10 ml of THF was shaken under an initial hydrogenpressure of 55 psi for 75 minutes. The catalyst was removed byfiltration and the filtrate was concentrated at reduced pressure to give0.10 g (83% yield, mp 88°-89°) ofN-[[3,5-bis-(tetradecyloxy)carbonyl]phenyl]glycine.

Anal. Calcd for C₃₈ H₆₅ NO₆ : C, 72.23; H, 10.37; N, 2.22. Found: C,72.54; H, 10.46; N, 2.26.

EXAMPLE 27 3,5-Didecylbenzenamine

To 5.2 g (0.011 mol) of nonyl triphenylphosphonium bromide suspended in100ml of anhydrous THF stirred in an ice bath under an argon atmospherewas added dropwise over 15 minutes 7.0 ml (0.011 mol) of 1.6M butyllithium inhexane. The reaction mixture was stirred in the ice bath for30 minutes anda solution of 0.97 g (0.0054 mol) of5-nitroisophthaldehyde in 15 ml of THFwas added dropwise over 15minutes. The reaction mixture was stirred at room temperature for 17hours and then the solvent was removed at reduced pressure. The residuewas treated with 10 ml of 1N HCl and the product wasextracted with ethylacetate. The dried extract was concentrated at reducedpressure and thecrude product was purified by chromatography on 100 g of silica gelusing 20% methylene chloride-hexane to give 1.79 g (78% yield) of thedesired olefin as an oil. This olefin and 0.5 g of 10% palladiumoncarbon in 75 ml of THF was shaken under an initial hydrogen pressureof 53 psi for 4 hours. The catalyst was removed by filtration and thefiltrate was concentrated under reduced pressure to give 1.6 g of3,5-didecylbenzenamine as a tan oil. The mass and nmr spectra wereconsistent with the structure.

Using this procedure, the reaction of octadecyl triphenylphosphoniumbromide and butyl lithium gave the Wittig reagent, which was allowed toreact with 5-nitroisophthaldehyde. The purified intermediate thusobtainedwas hydrogenated to yield 3,5-dinonadecylbenzenamine (mp51°-53°, Anal. Calcd for C₄₄ H₈₃ N: C, 84.40; H, 13.36; N, 2.24. Found:C, 84.46; H, 13.15; N, 2.18.

Using this procedure, the reaction of octadecyl triphenylphosphoniumbromide and butyl lithium gave the Wittig reagent, which was allowed toreact with 3-nitrobenzaldehyde. The purified intermediate thus obtainedwas hydrogenated to yield 3-nonadecylbenzenamine (mp 50°-51°, Anal.Calcd for C₂₅ H₄₅ N: C, 83.49; H, 12.61; N, 3.89. Found: C, 83.50; H,12.79; N, 3.86.

EXAMPLE 28 N-(3,5-Didecylphenyl)-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester

A mixture of 1.6 g (4.28 mmol) of 3,5-didecylbenzenamine, 6.8 ml (0.0428mol) of benzylbromoacetate, 3.0 g (0.021 mol) of potassium carbonate and0.65 g (4.28 mmol) of sodium iodide in 50 ml of DMF was stirred andheatedat 85° for 46 hours. The solvent was removed at reduced pressureandwater was added to the residue. The product was extracted with ethylacetate and the dried extract was concentrated at reduced pressure to anoil. Purification by HPLC using 10% ethyl acetate-hexane gave 1.69 g(59% yield) of N-(3,5-didecylphenyl)-N-[2-oxo-2-(phenylmethoxy)]glycinephenylmethyl ester as a yellow oil.

Anal. Calcd for C₄₄ H₆₃ NO₄ : C, 78.88; H, 9.48; N, 2.09. Found: C,78.71; H, 9.58; N, 1.97.

EXAMPLE 29 N-(Carboxymethyl)-N-(3,5-didecylphenyl)glycine

A mixture of 1.65 g ofN-(3,5-didecylphenyl)-N-[2-(phenylmethoxy)-2-oxoethyl]glycinephenylmethylester and 0.5 g of 10% palladium on carbon in 100 ml of THFwas shaken under an initial hydrogen pressure of 53 psi for 5 hours. Thecatalyst wasremoved by filtration and the filtrate was concentrated atreduced pressureto a solid which was recrystallized from methanol-waterto give 0.98 g (81%yield, mp 78°-81°) ofN-(carboxymethyl)-N-(3,5-didecylphenyl)glycine.

Anal. Calcd for C₃₀ H₅₁ NO₄.0.5H₂ O: C, 72.25; H, 10.51; N, 2.80; H₂ O,1.80. Found: C, 72.44; H,10.93; N, 2.65; H₂ O, 2.27.

EXAMPLE 30 4-[3,5-bis(decyloxy)phenyl]2,6-morpholinedione

To 2.0 g (3.83 mmol) ofN-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine in 100 ml ofmethylene chloride stirred at room temperature was added 0.9 g (4.37mmol)of dicyclohexylcarbodiimide The reaction mixture was stirred atroom temperature for 17 hours. After cooling in an ice bath, theprecipitate was removed by filtration and the filtrate was concentratedat reduced pressure to a solid which was recrystallized from hexane togive 1.7 g (88% yield, mp 62°-62°) of4-[3,5-bis(decyloxy)phenyl]2,6-morpholinedione.

Anal. Calcd for C₃₀ H₄₉ NO₅ : C, 71.53; H, 9.80; N, 2.78. Found: C,71.76; H, 10.03; N, 2.84.

EXAMPLE 31 N-(2-Methoxy-2-oxoethyl)-N-[3,5-bis(decyloxy)phenyl]glycine

A solution of 0.469 g of 4-[3,5-bis(decyloxy)phenyl]2,6-morpholinedionein 50 ml of methanol was warmed to 50° and then was left at roomtemperature for 17 hours. The solvent was removed at reduced pressure togive 0.44 g, mp 61°-62° of pureN-(2-methoxy-2-oxoethyl)-N-[3,5-bis(decyloxy )phenyl]glycine.

Anal. Calcd for C₃₁ H₅₃ NO₆ : C, 69.50; H, 9.97; N, 2.61. C,69.30; H,10.01; N, 2.62.

EXAMPLE 32 N-(Carbamoylmethyl)-N-[3,5-bis(decyloxy)phenyl]glycineammonium salt

Into a solution of 0.50 g of4-[3,5-bis(decyloxy)phenyl]2,6-morpholinedionedissolved in 50 ml ofmethylene chloride stirred at room temperature was bubbled ammonia gasfor 10 minutes. After standing at room temperature for17 hours, theprecipitate was removed by filtration to give 0.51 g, mp 149°-152° ofpure N-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine ammonium salt.

Anal. Calcd for C₃₀ H₅₂ N₂ O₅.NH₃ : C, 67.00; H, 10.31; N, 7.81. Found:C, 67.18; H, 10.29; N, 7.71.

EXAMPLE 33N-(2-Diethylaminoethoxy-2-oxoethyl)-N-[3,5-bis(decyloxy)phenyl]glycinemonohydrochloride salt

A solution of 0.43 g (0.85 mmol) of4-[3,5-bis(decyloxy)phenyl]2,6-morpholinedione and 0.23 ml (1.71 mmol)of N,N-diethylethanolamine in 40 ml of methylene chloride was kept atroom temperature for 3.5 days. The solvent was removed at reducedpressure and the residue was dissolved in ethyl acetate. The extract waswashed with water and then with 0.5N HCl, dried and concentrated atreduced pressure to a yellow foam which was dissolved in ether andcooled. Filtration gave 0.46 g (82% yield, mp 89°-91°) ofN-(2-diethylaminoethoxy-2-oxoethyl)-N-[3,5-bis(decyloxy)phenyl]glycinemonohydrochloride salt

Anal. Calcd for C₃₆ H₆₄ N₂ O₆.HCl: C, 65.78; H, 9.97; N, 4.26; Cl⁻,5.39. Found: C, 66.19; H, 10.17; N, 4.20; Cl⁻, 5.11.

EXAMPLE 34 3-(Octadecyloxy)benzenamine

a) A mixture of 4.0 g (0.029 mol) of 3-nitrophenol, 10.5 g (0.032 mol)of 1-bromooctadecane and 6.0 g (0.043 mol) of anhydrous potassiumcarbonate in 75 ml of anhydrous DMF was stirred and heated at 75° for 23hours. The solvent was removed at reduced pressure and water was addedto the residue. The product was extracted with ether and the driedextract was concentrated at reduced pressure to a solid which waspurified by HPLCusing 15% methylene chloride-hexane to give 9.0 g (80%yield) of 3-(octadecyloxy)nitrobenzene.

b) This was dissolved in 150 ml of THF, 2.0 g of 10% palladium on carbonwas added and the mixture was shaken under an initial hydrogen pressureof52 psi for 5.5 hours when uptake ceased. The catalyst was removed byfiltration and the filtrate was concentrated at reduced pressure to asolid which was recrystallized from methanol to give 7.7 g (92% yield,mp 77°-78°) of 3-(octadecyloxy)benzenamine.

The compounds in Table 9 were prepared by alkylation of 3-nitrophenolwith the required bromide using the procedure of Example 34a.Hydrogenation of the nitro compounds (in Table 9 ) as in procedure 34bgave the anilines inTable 10.

                                      TABLE 9                                     __________________________________________________________________________     ##STR37##                                                                                              Microanalytical Data                                                          Calcd    Found                                      Ex.                                                                              R           mp (°C.)                                                                    E.F.  C  H  N  C  H   N                                   __________________________________________________________________________    34a                                                                              OC.sub.10 H.sub.21                                                                        oil  C.sub.16 H.sub.25 NO.sub.3                                                                      N.O.*                                   34b                                                                              O(CH.sub.2).sub.2 O-2-Naphthyl                                                            110-112                                                                            C.sub.18 H.sub.15 NO.sub.4                                                          69.89                                                                            4.89                                                                             4.53                                                                             69.69                                                                            4.74                                                                              4.24                                34c                                                                              O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-C.sub.15 H.sub.31                                   49-51                                                                              C.sub.30 H.sub.45 NO.sub.4                                                          74.50                                                                            9.38                                                                             2.90                                                                             74.34                                                                            9.15                                                                              2.89                                __________________________________________________________________________    *Not obtained                                                             

                                      TABLE 10                                    __________________________________________________________________________     ##STR38##                                                                                              Microanalytical Data                                                          Calcd    Found                                      Ex.                                                                              R           mp (°C.)                                                                    E.F.  C  H  N  C  H   N                                   __________________________________________________________________________    34d                                                                              OC.sub.10 H.sub.21                                                                        49-52                                                                              C.sub.16 H.sub.27 NO                                                                            N.O.*                                   34e                                                                              O(CH.sub.2).sub.2 O-2-Naphthyl                                                            145-147                                                                            C.sub.18 H.sub.17 NO.sub.2                                                          77.40                                                                            6.13                                                                             5.01                                                                             77.28                                                                             6.19                                                                             4.87                                34f                                                                              O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-C.sub.15 H.sub.31                                   64-66                                                                              C.sub.30 H.sub.47 NO.sub.2                                                          79.42                                                                            10.44                                                                            3.09                                                                             79.04                                                                            10.50                                                                             3.15                                __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 35 N-(2-Methoxy-2-oxoethyl)-N-[3-octadecyloxy)phenyl]glycinemethyl ester

A mixture of 1.0 g (2.77 mmol) of 3-(octadecyloxy)benzenamine, 0.8 ml(8.3 mmol) of methyl bromoacetate, 1.5 g (6.9 mmol) of1,8-bis(dimethylamino)naphthalene and 0.116 g (0.78 mmol) of sodiumiodidein 15 ml of acetonitrile was stirred at reflux under an argonatmosphere for 20 hours. The reaction mixture was diluted with 50 ml oftoluene and washed with 0.05N HCl, with sainted NaHCO₃ solution driedand concentrated at reduced pressure to a solid which was recrystallizedfrom ether-hexane three times to give 0.61 g (44% yield, mp 75°-77°) ofN-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)phenyl]glycine methyl ester.

Anal. Calcd for C₃₀ H₅₁ NO₅ : C, 71.25; H, 10.16; N, 2.77. Found: C,71.01; H, 10.14; N, 2.83.

The compounds in Table 11 were prepared by the procedure of Example 35.

                                      TABLE 11                                    __________________________________________________________________________     ##STR39##                                                                                                  Microanalytical Data                                                          Calcd    Found                                  Ex.                                                                              R           R' mp (°C.)                                                                    E.F.   C  H  N  C  H  N                                __________________________________________________________________________    35a                                                                              OC.sub.10 H.sub.21                                                                        CH.sub.3                                                                         56-57                                                                              C.sub.22 H.sub.35 NO.sub.5                                                           67.15                                                                            8.96                                                                             3.56                                                                             67.12                                                                            9.17                                                                             3.48                             35b                                                                              OCOC.sub.17 H.sub.35                                                                      Bz 60-63                                                                              C.sub.42 H.sub.57 NO.sub.6                                                           75.08                                                                            8.55                                                                             2.08                                                                             74.92                                                                            8.61                                                                             2.11                             35c                                                                              OCONHC.sub.17 H.sub.35                                                                    Bz 63-64                                                                              C.sub.42 H.sub.58 N.sub.2 O.sub.6                                                    73.44                                                                            8.51                                                                             4.08                                                                             73.22                                                                            8.32                                                                             4.08                             35d                                                                              CONHC.sub.10 H.sub.21                                                                     CH.sub.3                                                                         72-74                                                                              C.sub.23 H.sub.36 N.sub.2 O.sub.5                                                    65.69                                                                            9.63                                                                             6.66                                                                             64.88                                                                            8.51                                                                             6.39                             35e                                                                              NHCONHC.sub.18 H.sub.37                                                                   Bz 72-75                                                                              C.sub.43 H.sub.61 N.sub.3 O.sub.5                                                    73.78                                                                            8.78                                                                             6.00                                                                             73.64                                                                            8.70                                                                             5.88                             35f                                                                              C.sub.19 H.sub.39                                                                         Bz oil  C.sub.43 H.sub.61 NO.sub.4                                                                    N.O.                                   35g                                                                              O(CH.sub.2).sub.2 O-2-Naphthyl                                                            Bz 69-71                                                                              C.sub.36 H.sub.33 NO.sub.6                                                           75.11                                                                            5.78                                                                             2.43                                                                             74.73                                                                            5.56                                                                             2.38                             35h                                                                              CONH-1-Adamantyl                                                                          Bz 115-117                                                                            C.sub.35 H.sub.38 N.sub.2 O.sub.5                                                    74.18                                                                            6.76                                                                             4.94                                                                             74.10                                                                            6.80                                                                             4.88                             35i                                                                              O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-C.sub.15 H.sub.31                                   Bz 51-53                                                                              C.sub.48 H.sub.63 NO.sub.6                                                           76.87                                                                            8.47                                                                             1.87                                                                             77.06                                                                            8.37                                                                             1.76                             __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 36 N-(Carboxymethyl)-N-[3-(octadecyloxy)phenyl]glycine

A solution of 0.56 g (1.11 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)phenyl]glycine methyl esterand 4.4 ml (4.4 mmol) of 1N NaOH in 50 ml of methanol was stirred atreflux under an talon atmosphere for 75 minutes. After standing at roomtemperature for 17 hours the precipitate was removed by filtration. Thesolid was suspended in 100 ml of 1N HCl and extracted with ethylacetate. The dried extract was concentrated at reduced pressure and theresultant solid was recrystallized from methanol-water to give 0.31 g(60% yield, mp135°-138°) ofN-(carboxymethyl)-N-[3-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₂₈ H₄₇ NO₅ : C, 70.40; H, 9.92; N; 2.93. Found: C,70.75; H, 10.23; N, 2.97.

The compounds in Table 12 were prepared using the procedure of Example36 if the precursor was a methyl ester or the procedure of Example 38 ifthe precursor was a benzyl ester.

                                      TABLE 12                                    __________________________________________________________________________     ##STR40##                                                                                               Microanalytical Data                                                          Calcd    Found                                     Ex.                                                                              R           mp (°C.)                                                                    E.F.   C  H  N  C  H  N                                   __________________________________________________________________________    36a                                                                              OC.sub.10 H.sub.21                                                                        142-145                                                                            C.sub.20 H.sub.31 NO.sub.5                                                           65.73                                                                            8.55                                                                             3.83                                                                             85.66                                                                            8.76                                                                             3.85                                36b                                                                              OCOC.sub.17 H.sub.35                                                                      131-133                                                                            C.sub.28 H.sub.45 NO.sub.6                                                           68.40                                                                            9.23                                                                             2.85                                                                             68.15                                                                            9.49                                                                             3.01                                36c                                                                              OCONHC.sub.17 H.sub.35                                                                    166-169                                                                            C.sub.28 H.sub.46 N.sub.2 O.sub.6                                                    66.37                                                                            9.15                                                                             5.53                                                                             66.40                                                                            9.05                                                                             5.62                                36d                                                                              CONHC.sub.10 H.sub.21                                                                     152-154                                                                            C.sub.21 H.sub.32 N.sub.2 O.sub.5                                                    64.26                                                                            9.22                                                                             7.14                                                                             64.27                                                                            8.37                                                                             7.13                                36e                                                                              NHCONHC.sub.18 H.sub.37                                                                   152-155                                                                            C.sub.29 H.sub.49 N.sub.3 O.sub.5                                                    67.02                                                                            9.50                                                                             8.08                                                                             67.23                                                                            9.56                                                                             8.10                                36f                                                                              C.sub.19 H.sub.39                                                                         123-125                                                                            C.sub.29 H.sub.49 NO.sub.4                                                           73.22                                                                            10.38                                                                            2.94                                                                             73.18                                                                            10.43                                                                            2.97                                36g                                                                              O(CH.sub.2).sub.2 O-2-Naphthyl                                                            147-149                                                                            C.sub.22 H.sub.21 NO.sub.6                                                           66.25                                                                            5.35                                                                             3.54                                                                             66.90                                                                            5.47                                                                             3.51                                36h                                                                              CONH-1-Adamantyl                                                                          154-156                                                                            C.sub.21 H.sub.26 N.sub.2 O.sub.5                                                    65.27                                                                            6.78                                                                             7.25                                                                             65.20                                                                            6.67                                                                             7.37                                36i                                                                              O(CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-C.sub.15 H.sub.31                                   129-132                                                                            C.sub.34 H.sub.51 NO.sub.6                                                           71.67                                                                            9.02                                                                             2.06                                                                             71.53                                                                            9.17                                                                             2.35                                __________________________________________________________________________

EXAMPLE 37N-[3-(Octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester

A mixture of 5.5 g (0.015 mol) of 3-(octadecyloxy)benzenamine, 7.3 ml(0.046 mol) of benzyl bromoacetate, 8.2 g (0.038 mol) of1,8-bis(dimethylamino)naphthalene, 0.64 g (4.26 mmol) of sodium iodidein 100 ml of anhydrous acetonitrile and 25 ml of anhydrous DMF wasstirred atreflux under an argon atmosphere for 48 hours. The solventswere removed atreduced pressure and the residue was dissolved in ethylacetate and washed with 0.05N HCl, with saturated NaHCO₃ solution driedand concentratedat reduced pressure. Purification by HPLC using 15%ethyl acetate-hexane gave, after recrystallization of the combined purefractions from ether-hexane, 6.56 g (69% yield, mp 55°-57°) ofN-[3-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester.

Anal. Calcd for C₄₂ H₅₉ NO₅ : C, 76.67; H, 9.04; N, 2.13. Found: C,76.40; H, 9.01; N, 1.78.

EXAMPLE 38 N-(Carboxymethyl)-N-[3-(octadecyloxy)phenyl]glycine from thephenylmethyl ester

A mixture of 6.9 g (0.01 mol) ofN-[3-(octadecyloxy)phenyl]-N-2[-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester and 1.0 g of 10% palladium on carbon in 150 ml of THFwas shaken under an initial hydrogen pressure of 50 psi until uptakeceased after 5 hours. The catalyst was removed by filtration and thefiltrate was concentrated at reduced pressure to a solid which wasrecrystallized from ethyl acetate to give 4.43 g (88% yield, mp130°-133°) of N-(carboxymethyl)-N-[3-(octadecyloxy)phenyl]glycine.

EXAMPLE 39 N-(Carboxymethyl)-N-(4-tetradecylphenyl)glycine

A mixture of 1.0 g (3.45 mmol) of 4-tetradecylphenyl aniline (AldrichChemical Company), 5.0 ml (0.052 mol) of methyl bromoacetate, 0.95 g(6.9 mmol) of potassium carbonate and 0.5 g (3.45 mmol) of sodium iodidein 15 ml of DMF was stirred and heated at 100° for 45 hours. The solventwas removed at reduced pressure and water was added to the residue. Theproduct was extracted with ethyl acetate and the extract was washed withsodium bisulfite solution, dried and concentrated. The residue waspurified by chromatography on silica gel using 25% ethyl acetate-hexanetogive 0.7 g of N-(2-methoxy-2-oxoethyl)-N-(4-tetradecylphenyl)glycinemethylester. This dimethyl ester was hydrolyzed by treatment with 1.5 mlof 6N NaOH in 50 ml of methanol. The mixture was warmed briefly todissolve the ester and then was kept at room temperature for 3 days. Thesolvent was removed at reduced pressure and the residue was acidified topH 2. The product was extracted with ethyl acetate and the dried extractwas concentrated at reduced pressure to a solid which was recrystallizedfrom methanol-water to give 0.26 g, mp 160°-165°, ofN-carboxymethyl)-N-(4-tetradecylphenyl)glycine.

Anal. Calcd for C₂₄ H₃₉ NO₄ : C, 71.07; H, 9.69; N, 3.45. Found: C,70.58; H, 9.73; N, 3.43.

The compounds in Table 13 were prepared using the procedure of Example39.

                                      TABLE 13                                    __________________________________________________________________________     ##STR41##                                                                                        Microanalytical Data                                                          Calcd     Found                                           Ex.                                                                              R    mp (°C.)                                                                    E.F.   C  H   N  C  H   N                                        __________________________________________________________________________    39a                                                                              H    152-154                                                                            C.sub.10 H.sub.11 NO.sub.4                                                           known compound                                            39b                                                                              C.sub.4 H.sub.9                                                                    107-109                                                                            C.sub.14 H.sub.19 NO.sub.4                                                           63.38                                                                            7.22                                                                              5.28                                                                             63.52                                                                            7.31                                                                              5.27                                     39c                                                                              C.sub.8 H.sub.17                                                                   130-140                                                                            C.sub.18 H.sub.27 NO.sub.4                                                           67.26                                                                            8.47                                                                              4.36                                                                             66.73                                                                            8.23                                                                              4.38                                     39d                                                                              C.sub.10 H.sub.21                                                                  112-115                                                                            C.sub.20 H.sub.31 NO.sub.4                                                           68.74                                                                            8.94                                                                              4.01                                                                             68.38                                                                            8.84                                                                              3.96                                     __________________________________________________________________________

EXAMPLE 40 3-Amino-N-octadecylbenzamide

To a mixture of 1.45 g (5.38 mmol) of octadecylamine and 1.1 ml (8 mmol)oftriethylamine in 20 ml of methylene chloride stirred and cooled in anice bath was added 1.00 g (5.38 mmol) of 3-nitrobenzoyl chloride in 30ml of methylene chloride. The reaction mixture was stirred at roomtemperature for 17 hours and then was washed with 1N HCl. Some of theproduct was insoluble and was removed by filtration. The methylenechloride layer was concentrated at reduced pressure to give additionalproduct which was combined with the original insoluble product andrecrystallized from methanol to give 0.86 g, mp 98°-99°, of3-nitro-N-octadecylbenzamide. This and 0.3 g of 10% palladium on carbonin125 ml of THF was shaken under an initial hydrogen pressure of 52 psiuntiluptake ceased after 75 minutes. The catalyst was removed byfiltration and the residue was recrystallized from methanol-water togive 0.6 g, mp 76°-77°, of 3-amino-N-octadecylbenzamide.

Anal. Calcd for C₂₅ H₄₄ N₂ O: C, 77.26; H, 11.41; N, 7.21. Found: C,77.07; H, 11.24; N, 7.03.

Using this procedure 3-nitrobenzoyl chloride was treated with decylaminetogive 3-nitro-N-decylbenzamide, mp 86°-88°, which was hydrogenated togive 3-amino-N-decylbenzamide, mp 56°-58°, which gave nmr and massspectra consistent with the structure.

Using this procedure 3-nitrobenzoyl chloride was treated with1-adamantanamine to give 3-nitro-N-tricyclo[3.3.1.1/3,7/]dec-1-ylbenzamide (mp 157°-159°, Anal. Calcd for C₁₇ H₂₀N₂ O₃ : C, 67.98;; H, 6.71; N, 9.33. Found: C, 67.22; H, 6.68; N, 9.34)which was hydrogenated to give 3-amino-N-tricyclo[3.3.1.1/3,7/]dec-1-ylbenzamide (mp 172°-173°, Anal. Calcd for C₁₇ H₂₂N₂ O: C, 75.52; H, 8.20; N, 10.36. Found: C, 75.47; H, 8.27; N, 10.35.

EXAMPLE 41N-[3-[(Octadecylamino)carbonyl]phenyl-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester

A mixture of 0.6 g (1.54 mmol) of 3-amino-N-octadecylbenzamide 1.2 ml(7.72mmol) of benzyl bromoacetate, 1.32 g (6.16 mmol) of1,8-bis(dimethylamino)naphthalene and 0.23 g (1.54 mmol) of sodiumiodide in 40 ml of acetonitrile was stirred at reflux for 65 hours. Thesolvent was removed at reduced pressure and the residue was dissolved inethyl acetate and washed with 0.05N HCl, with saturated NaHCO₃ solution,dried and concentrated to a solid. Chromatography on 70 g of 230-400mesh silica gel using 30% ethyl acetate-hexane gave 0.4 g (38% yield, mp70°-71°) ofN-3-[(octadecylamino)carbonyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester.

Anal. Calcd for C₄₃ H₆₀ N₂ O₅ : C, 75.40; H, 8.83; N, 4.09. Found: C,75.13; H, 8.83: N, 4.19.

EXAMPLE 42N-(Carboxymethyl)-N-[3-(octadecylamino)carbonyl]phenyl]glycine

A mixture of 0.4 g ofN-3-[(octadecylamino)carbonyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester and 0.2 g of 10% palladium on carbon in 40 ml ofethyl acetate was shaken under an initial hydrogen pressure of 53 psiuntil uptake ceased after 2 hours. The catalyst was removed byfiltration and the filtrate was concentrated at reduced pressure to asolid which was recrystallized from methanol-water to give 0.22 g, mp143°-147°, ofN-(carboxymethyl)-N-[3-(octadecylamino)carbonyl]phenyl]glycine.

Anal. Calcd for C₂₉ H₄₈ N₂ O₅ : C, 69.01; H, 9.59; N, 5.55. Found: C,68.96; H, 9.57; N, 5.54.

EXAMPLE 43 N-(3-Nitrophenyl)octadecanamide

To 2.0 g (14.5 mmol) of 3-nitroaniline and 4.5 ml (32 mmol) oftriethylamine in 60 ml of methylene chloride stirred at room temperaturewas added 5.4 ml (16 mmol) of octadecanoyl chloride in 10 ml ofmethylene chloride. The reaction mixture was kept at room temperaturefor 18 hours and then was washed with 1N HCl, dried and concentrated atreduced pressure to a solid. Recrystallization from methanol gave 5.6 g(95% yield, mp 75°-76°) of N-(3-nitrophenyl) octadecanamide.

Anal. Calcd for C₂₄ H₄₀ N₂ O₃ : C, 71.25; H, 9.97; N, 6.92. Found: C,71.10; H, 10.25; N, 6.70.

EXAMPLE 44 N-(3-Aminophenyl)octadecanamide

A mixture of 5.5 g of N-(3-nitrophenyl)octadecanamide and 0.6 g of 10%palladium on carbon in 100 ml of ethyl acetate was shaken under aninitialhydrogen pressure of 52 psi until uptake ceased after 23 hours.The catalyst was removed by filtration and the filtrate was concentratedat reduced pressure to a solid which was recrystallized frommethanol-water to give 4.6 g (90% yield, mp 98°-102°) ofN-(3-aminophenyl)octadecanamide.

Anal. Calcd for: C₂₄ H₄₂ N₂ O: C, 76.95; H, 11.30; N, 7.48. Found: C,76.90; H, 11.27; N, 7.56.

EXAMPLE 45 N-(2-Methoxy-2-oxoethyl)-N-[3-[(1-oxooctadecyl)amino]phenyl]glycine methylester

A mixture of 2.0 g (5.3 mmol) of N-(3-aminophenyl)octadecanamide, 2.5 ml(26.5 mmol) of methyl bromoacetate, 4.5 g (21 mmol) of1,8-bis(dimethylamino)naphthalene and 0.8 g (5.3 mmol) of sodium iodidein100 ml of acetonitrile was stirred at reflux under an argon atmospherefor 46 hours. The solvent was removed at reduced pressure and theresidue was dissolved in ethyl acetate. The extract was washed with0.05N HCl, dried and concentrated at reduced pressure to a solid whichwas recrystallized twice from methanol-water to give 1.83 g (67% yield,mp 78°-79°) ofN-(2-methoxy-2-oxoethyl)-N-[3-[(1-oxooctadecyl)amino]phenyl]glycinemethylester.

Anal. Calcd for C₃₀ H₅₀ N₂ O₅ : C, 69.46; H, 9.72; N, 5.40. Found: C,69.45; H, 9.48; N, 5.31.

EXAMPLE 46 N-(Carboxymethyl)-N-[3-[(1-oxooctadecyl)amino]phenyl]glycine

A mixture of 1.8 gN-(2-methoxy-2-oxoethyl)-N-[3-[(1-oxooctadecyl)amino]phenyl]glycinemethylester and 2.4 ml of 6N NaOH in 30 ml of dioxane and 30 ml ofmethanol was heated to dissolve the solid and left at room temperaturefor 18 hours. The solid which precipitated was filtered, treated with 1NHCl and filtered again. Recrystallization from methanol-THF-water gave1.35 g (79%yield, mp 133°-140°) ofN-(carboxymethyl)-N-[3-[(1-oxooctadecyl)amino]phenyl]glycine.

Anal. Calcd for C₂₈ H₄₆ N₂ O₅ : C,68.54; H,9.45; N,5.71. Found: C,68.59; H, 9.63; N, 5.72.

EXAMPLE 47 N-(3-Hydroxyphenyl)-N-(2-methoxy-2-oxoethyl(glycine methylester

A mixture of 1.85 g (9.3 mmol) of 3-benzyloxyaniline, 4.4 ml (46.5 mmol)ofmethyl bromoacetate, 8.0 g (37 mmol) of1,8-bis(dimethylamino)naphthalene and 1.4 g (9.3 mmol) of sodium iodidein 100 ml of acetonitrile was stirred at reflux for 41 hours. Thesolvent was removed at reduced pressure and the residue was dissolved inethyl acetate. The extract was washed with 0.05N HCl, with saturatedNaHCO₃ solution, dried and concentrated to an oil. Purification bychromatography on silica gel using30% ethyl acetate-hexane gave 2.73 g(88% yield) ofN-[3-(phenylmethoxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methylester. The nmr and mass spectra were consistent with the structure. Thismaterialand 0.5 g of 10% palladium on carbon in 60 ml of ethyl acetatewas shaken under an initial hydrogen pressure of 53 psi until uptakeceased after 24 hours. The catalyst was removed by filtration and thefiltrate was concentrated at reduced pressure to an oil which waspurified by chromatography on silica gel using 50% ethyl acetate-hexaneto give 1.15 g(58% yield) ofN-(3-hydroxyphenyl)-N-[2-methoxy-2-oxoethyl)glycine methyl ester as anoil. The nmr spectrum was consistent with the structure.

EXAMPLE 48N-(2-Methoxy-2-oxoethyl)-N-[3-[(Z)-(9-octadecenyl)oxy]phenyl]glycinemethylester

A mixture of 0.24 g (0.95 mmol) ofN-(3-hydroxyphenyl)-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 0.33 g(1 mmol) of oleyl bromide, 0.15 g (1 mmol) of sodium iodide and 0.41 g(3 mmol) of potassium carbonate in 10 ml of acetone was stirred atreflux under argon for 18 hours. DMF (5 ml) was added and reflux wascontinued for 3 days. The solvents were removed at reduced pressure andthe residue was dissolved in ethyl acetate. The extract was dried andconcentrated at reduced pressure to an oil which was purified bychromatography on 230-400mesh silica gel using 25% ethyl acetate-hexaneto give 0.25 g (50% yield, mp 36°-37°) of N-(2-methoxy-2-oxoethyl)-N-[3-[(Z)-(9-octadecenyl)oxy]phenyl]glycine methyl ester.The nmr and mass spectra were consistent with the structure.

Using this procedure, the reaction ofN-(3-hydroxyphenyl-N-(2-methoxy-2-oxoethyl)glycine methyl ester withlinoleyl bromide gave N-(2-methoxy-2-oxoethyl)-N-[3-[(9Z,12Z)-(9,12-octadecadienyl]oxy]phenyl]glycine methyl ester as an oil. Thestructure was confirmed by nmr and mass spectra.

EXAMPLE 49 N(Carboxymethyl)-N-[3-[(Z)-9-octadecenyl)oxy]phenyl]glycine

A mixture of 0.29 g (0.57 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-[(Z)-(9-octadecenyl)oxy]phenyl]glycinemethyl ester and 0.4 ml (2.4 mmol) of 6N NaOH in 2 ml of dioxane and 10mlof methanol was warmed to dissolve the solid and left at roomtemperature for 16 hours. The solid was stirred with 1N HCl, filteredagain and recrystallized from ethyl acetate-methanol-hexane to give 0.22g, mp 128°-135°, of N-(carboxymethyl)-N-[3-(Z)-(9-octadecenyl)oxy]phenylglycine. The nmr and mass spectra were consistent with thestructure.

Using this procedure, base hydrolysis ofN-(2-methoxy-2-oxoethyl)-N-[3-[(9Z, 12Z)-(9,12-octadecadienyl]oxy]phenyl]glycine methyl ester gaveN-(carboxymethyl)-N-[3-[(9Z,12Z)-(9,12-octadecadienyl]oxy]phenyl]glycine as a semisolid. Thestructure was confirmed by nmr and mass spectra.

EXAMPLE 50 N-(3-Aminophenyl)-N-(2-methoxy-2-oxoethyl)glycine methylester

A mixture of 5.0 g (0.036 mol) of 3-nitroaniline, 11 ml (0.11 mol) ofmethyl bromoacetate and 10 ml of diisopropylmethyl amine in 10 ml ofacetonitrile was stirred at reflux under an argon atmosphere for 3 days.The solvent was removed at reduced pressure and the residue wasdissolved in ethyl acetate and washed with 0.1N HCl, with saturatedNaHCO₃ solution, dried and concentrated at reduced pressure to an oil.Purification by HPLC using 5% ethyl acetate-hexane gave 4.95 g(49%yield, mp 54°-57°) of N-(3-nitrophenyl)-N-(2-methoxy-2-oxoethyl)glycinemethyl ester. The nmr spectrum was consistent with the structure. Thismaterial and 0.5 g of 10%palladium on carbon in 100 ml of ethyl acetatewas shaken under an initial hydrogen pressure of 53 psi for 23 hours.The catalyst was removed by filtration and the filtrate was concentratedat reduced pressure to 4.0 g of pureN-(3-aminophenyl)-N-(2-methoxy-2-oxoethyl)glycine methyl ester. The nmrspectrum was consistent with the structure.

EXAMPLE 51N-(Carboxymethyl)-N-[3-[(Z)-(1-oxo-9-octadecenyl)amino]phenyl]glycine

To a solution of 0.486 g (1.94 mmol) ofN-(3-aminophenyl)-N-(2-methoxy-2-oxoethyl) glycine methyl ester and 0.56ml (4 mmol) of triethylamine in 25 ml of methylene chloride stirred atroom temperature was added 0.86 ml (2.6 mmol) of oleoyl chloride (70%).The reaction mixture was stirred at room temperature for 3 hours andthen was washed with 1N HCl, dried and concentrated to an oil.Purification by chromatography on silica gel using 50% ethylacetate-hexane gave 0.97 gofN-(2-methoxy-2-oxoethyl)-N-3-[(Z)-(1-oxooctadecenyl)amino]phenyl]glycinemethyl ester. This material was hydrolyzed by treatment with 1.6 ml (9.6mmol) of 6N NaOH in 20 ml of methanol and 10 ml of dioxane at roomtemperature for 17 hours. The solvents were removed at reduced pressureand the residue was stirred with excess 1N HCl. The product was removedbyfiltration and recrystallized from methanol-water to give 0.75 g ofN-(carboxymethyl)-N-[3-[(Z)-(1-oxo-9-octadecenyl)amino]phenyl]glycine asawaxy solid.

Anal. Calcd for C₂₈ H₄₄ N₂ O₅ : C, 68.82; H, 9.08; N, 5.73. Found: C,67.60; H, 8.79; N, 5.49.

Using this procedure, the reaction ofN-(3-aminophenyl)-N-(2-methoxy-2-oxoethyl)glycine methyl ester withlinoleyl chloride gave N-(carboxymethyl)-N-[3-[(9Z,12Z)-(1-oxo-9,12-octadecadienyl)amino]phenyl]glycine (mp 135°-140°,Anal. Calcd for C₂₈ H₄₂ N₂ O₅: C, 69.11; H, 8.70; N, 5.76. Found: C,69.03; H, 8.79; N, 5.79.

EXAMPLE 52 3-Hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester

A mixture of 30 g (0.123 mol) of 3,5-dihydroxybenzoic acid phenylmethylester, 40.9 g (0.123 mol) of 1-bromooctadecane, 17 g (0.123 mol) ofanhydrous potassium carbonate in 500 ml of acetone and 10 ml of DMF wasstirred at reflux for 25 hours. The reaction mixture was filtered andthe filtrate was concentrated at reduced pressure to a solid. Theresidue was treated with water and the product was extracted withmethylene chloride. The dried extract was concentrated at reducedpressure to a solid which was purified by HPLC using 1% ethylacetate-methylene chloride to give 22 g (36% yield, mp 72°-75°) of3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester. The structurewas confirmed by nmr and mass spectra.

EXAMPLE 53 3-(Octadecyloxy)-5-(3-phenoxypropoxy)benzoic acidphenylmethyl ester

A mixture of 12 g (0.024 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acidphenylmethyl ester, 6 ml (0.038 mol) of 3-phenoxypropyl bromide, 3.6 g(0.024 mol) of sodium iodide and 10 g (0.072 mol) of potassium carbonatein 400 ml of acetone and 80 ml of DMF was stirred at reflux for 46hours. The reaction mixture was filtered and the filtrate wasconcentrated to dryness at reduced pressure. Water was added to theresidue and the product was extracted with ethyl acetate. The driedextract was concentrated at reduced pressure to an oil which waspurified by HPLC using 5% ethyl acetate-hexane. The pure fractions werecombined, triturated with hexane and filtered to give 14.6 g (96% yield,mp 46°-47°) of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzoic acidphenylmethyl ester. The structure was confirmed by nmr and mass spectra.

Anal. Calcd for C₄₁ H₅₈ O₅ : C, 78.05; H, 9.27. Found: C, 77:89; H,9.03.

The compounds in Table 14 were prepared using the procedure of Example53.

                                      TABLE 14                                    __________________________________________________________________________     ##STR42##                                                                                                    Microanalytical Data                                                          Calcd    Found                                Ex.                                                                              R              R' mp (°C.)                                                                    E.F.  C  H  N  C  H   N                             __________________________________________________________________________    53a                                                                              (CH.sub.2).sub.2 OH                                                                          Bz 47-49                                                                              C.sub.34 H.sub.52 O.sub.5                                                                       N.O.                              53b                                                                              (CH.sub.2).sub.2 OAc                                                                         Bz 44-46                                                                              C.sub.36 H.sub.54 O.sub.6                                                                       N.O.                              53c                                                                              CH.sub.2 COOCH.sub.3                                                                         Bz 56-58                                                                              C.sub.35 H.sub.52 O.sub.6                                                           73.91                                                                            9.21  74.00                                                                            9.04                              53d                                                                              (CH.sub.2).sub.4 COOCH.sub.3                                                                 Bz 40-42                                                                              C.sub.38 H.sub.58 O.sub.6                                                                       N.O.                              53e                                                                              (CH.sub.2).sub.10 COOCH.sub.3                                                                Bz 37-38                                                                              C.sub.44 H.sub.70 O.sub.6                                                           76.04                                                                            10.15 76.03                                                                            10.33                             53f                                                                              CO-1-Adamantyl Bz oil                    N.O.                              53g                                                                              COCH(C.sub.6 H.sub.5).sub.2                                                                  Bz 47-49                                                                              C.sub.46 H.sub.58 O.sub.5                                                                       N.O.                              53h                                                                              (CH.sub.2).sub.2 O-2-Naphthyl                                                                Bz 62-65                                                                              C.sub.44 H.sub.58 O.sub.5                                                           79.24                                                                            8.77  78.90                                                                            8.93                              53i                                                                              (CH.sub.2).sub.3 O-3-Pyridyl                                                                 Bz 43-45                                                                              C.sub.40 H.sub.57 NO.sub.5                                                          76.03                                                                            9.09                                                                             2.22                                                                             76.33                                                                            9.10                                                                              2.22                          53j                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-OCH.sub.3                                               Bz 54-55                                                                              C.sub.42 H.sub.60 O.sub.6                                                                       N.O.                              53k                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OCH.sub.3                                               Bz 45-49                                                                              C.sub.42 H.sub.60 O.sub.6                                                                       N.O.                              53l                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OBz                                                     CH.sub.3                                                                         75-77                                                                              C.sub.42 H.sub.60 O.sub.6                                                           76.33                                                                            9.15  76.04                                                                            9.09                              53m                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-NO.sub.2                                                CH.sub.3                                                                         76-78                                                                              C.sub.35 H.sub.53 NO.sub.7                                                          70.09                                                                            8.91                                                                             2.34                                                                             69.89                                                                            8.99                                                                              2.27                          53n                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-COOCH.sub.3                                             Bz 59-61                                                                              C.sub.43 H.sub.60 O.sub.7                                                           79.97                                                                            8.78  74.99                                                                            8.79                              53o                                                                              (CH.sub.2).sub.2 O(CH.sub.2).sub.2 O(CH.sub.2).sub.2                                         Bz.sub.2 H.sub.5                                                                 oil  C.sub.40 H.sub.64 O.sub.7                                                                       N.O.                              __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 54 3-(Octadecyloxy)-5-(3-phenoxypropoxy)benzoic acid

A mixture of 14.6 g of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzoic acidphenylmethyl ester and 3 g of 10% palladium on carbon was shaken in ahydrogen atmosphere at room temperature for 2 hours. The catalyst wasremoved by filtration and the filtrate was concentrated to a solid whichwas recrystallized from ether-hexane to give 11.8 g (95% yield mp79°-81°) of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzoic acid.

Anal. Calcd for C₃₄ H₅₂ O₅ : C, 75.52; H, 9.69. Found: C, 75.09; H,9.80.

The compounds in Table 15 were prepared using the procedure of Example54 if the precursor was a benzyl ester or by basic hydrolysis usingsodium hydroxide, if the precursor was a methyl ester.

                                      TABLE 15                                    __________________________________________________________________________     ##STR43##                                                                                                 Microanalytical Data                                                          Calcd    Found                                   Ex.                                                                              R              mp (°C.)                                                                    E.F.  C  H  N  C  H   N                                __________________________________________________________________________    54a                                                                              (CH.sub.2)OAc  68-71                                                                              C.sub.29 H.sub.48 O.sub.6                                                                       N.O.                                 54b                                                                              (CH.sub.2).sub.2 OH                                                                          105-106                                                                            C.sub.27 H.sub.46 O.sub.5                                                           71.96                                                                            10.29 72.00                                                                            10.09                                54c                                                                              CH.sub.2 COOCH.sub.3                                                                         95-97                                                                              C.sub.28 H.sub.46 O.sub.6                                                           70.26                                                                            9.69  70.00                                                                            9.73                                 54d                                                                              (CH.sub.2).sub.10 COOCH.sub.3                                                                68-71                                                                              C.sub.37 H.sub.64 O.sub.6                                                           73.47                                                                            10.66 73.26                                                                            10.97                                54e                                                                              CO-1-Adamantyl 44-47                                                                              C.sub.36 H.sub.56 O.sub.5                                                           76.01                                                                            9.92  76.15                                                                            10.21                                54f                                                                              COCH(C.sub.6 H.sub.5).sub.2                                                                  83-86                                                                              C.sub.39 H.sub.52 O.sub.5                                                           77.96                                                                            8.72  77.63                                                                            8.79                                 54g                                                                              (CH.sub.2).sub.2 O-2-Naphthyl                                                                 98-103                                                                            C.sub. 37 H.sub.52 O.sub.5                                                          77.04                                                                            9.09  76.81                                                                            9.22                                 54h                                                                              (CH.sub.2).sub.3 O-3-Pyridyl                                                                 93-94                                                                              C.sub.33 H.sub.51 NO.sub.5                                                          73.16                                                                            9.49                                                                             2.59                                                                             73.17                                                                            9.45                                                                              3.07                             54i                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.5                                                            79-81                                                                              C.sub.34 H.sub.52 O.sub.5                                                           75.52                                                                            9.69  75.09                                                                            9.80                                 54j                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OCH.sub.3                                               86-87                                                                              C.sub.35 H.sub.54 O.sub.6                                                           73.65                                                                            9.54  73.85                                                                            9.73                                 54k                                                                              (CH2)3OC6H4-4-OBz                                                                             99-101                                                                            C.sub.41 H.sub.58 O.sub.6                                                           76.12                                                                            9.04  75.92                                                                            9.02                                 54l                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OH                                                      92-95                                                                              C.sub.34 H.sub.52 O.sub.6                                                           73.35                                                                            9.41  73.07                                                                            9.43                                 54m                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-NO.sub.2                                                91-93                                                                              C.sub.34 H.sub.51 NO.sub.7                                                          69.71                                                                            8.78                                                                             2.39                                                                             69.53                                                                            8.84                                                                              2.33                             54n                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-COOCH.sub.3                                             88-90                                                                              C.sub.36 H.sub.54 O.sub.7                                                           72.21                                                                            9.09  72.02                                                                            9.17                                 54o                                                                              (CH.sub.2).sub.2 O(CH.sub.2).sub.2 O(CH.sub.2).sub.2 OC.sub.2 H.sub.5                        38-40                                                                              C.sub.33 H.sub.58 O.sub.7                                                           69.93                                                                            10.31 69.62                                                                            10.15                                __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 55 3-(Octadecyloxy)-5-(3-phenoxypropoxy)phenylcarbamic acidphenylmethyl ester

To a suspension of 10.7 g (0.02 mol)3-(octadecyloxy)-5-(3-phenoxypropoxy)benzoic acid in 250 ml of anhydroustoluene cooled in an ice bath was added 5.1 ml (0.024 mol) ofdiphenylphosphoryl azide followed by 3.8 ml (0.028 mol) oftriethylamine. The reaction mixture was stirred in an ice bath for 1hour and then heatedat 90° for 2 hours. After cooling to roomtemperature, 70 ml of benzyl alcohol was added. The reaction mixture wasthen stirred and heatedat 90° for 18 hours. The solvent was removed atreduced pressure andthe residue was dissolved in ethyl acetate. Theextract was washed with saturated NaHCO₃ solution, dried andconcentrated to an oil which waspurified by HPLC using 10% ethylacetate-hexane to give 10.9 g (85% yield, mp 68°-69°) of3-(octadecyloxy)-5-(3-phenoxypropoxy)phenylcarbamic acid phenylmethylester. The structure was confirmed by nmr and mass spectra.

The compounds in Table 16 were prepared using the procedure of Examples55,except for the compounds 55j and k, which were prepared using t-butylalcohol in place of benzyl alcohol.

                                      TABLE 16                                    __________________________________________________________________________     ##STR44##                                                                                                   Microanalytical Data                                                          Calcd    Found                                 Ex.                                                                              R            R' mp (°C.)                                                                    E.F.   C  H  N  C  H  N                               __________________________________________________________________________    55a                                                                              (CH.sub.2).sub.2 OAc                                                                       Bz 45-52                                                                              C.sub.36 H.sub.55 NO.sub.6                                                                       N.O.                               55b                                                                              CH.sub.2 COOCH.sub.3                                                                       Bz 81-84                                                                              C.sub.35 H.sub.53 NO.sub.6                                                                       N.O.                               55c                                                                              (CH.sub.2).sub.10 COOCH.sub.3                                                              Bz 46-48                                                                              C.sub.44 H.sub.71 NO.sub.6                                                           74.43                                                                            10.08                                                                            1.97                                                                             74.00                                                                            9.60                                                                             1.64                            55d                                                                              CO-1-Adamantyl                                                                             Bz oil  C.sub.43 H.sub.63 NO.sub.5                                                                       N.O.                               55e                                                                              COCH(C.sub.6 H.sub.5).sub.2                                                                Bz oil  C.sub.46 H.sub.59 NO.sub.5                                                                       N.O.                               55f                                                                              (CH.sub.2).sub.2 O-2-Naphthyl                                                              Bz 95-97                                                                              C.sub.44 H.sub.59 NO.sub.5                                                           77.50                                                                            8.72                                                                             2.05                                                                             77.66                                                                            8.94                                                                             2.06                            55g                                                                              (CH.sub.2).sub.2 O-3-Pyridyl                                                               Bz 65-67                                                                              C.sub.40 H.sub.58 N.sub.2 O.sub.5                                                                N.O.                               55h                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-OCH.sub.3                                             Bz 58-60                                                                              C.sub.42 H.sub.61 NO.sub.5                                                                       N.O.                               55i                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OCH.sub.3                                             Bz 70-71                                                                              C.sub.42 H.sub.61 NO.sub.6                                                                       N.O.                               55j                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OBz                                                   tBu                                                                              90-92                                                                              C.sub.45 H.sub.67 NO.sub.6                                                                       N.O.                               55k                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-NO.sub.2                                              tBu                                                                               98-100                                                                            C.sub.38 H.sub.60 N.sub.2 O.sub.7                                                                N.O.                               55l                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-COOCH.sub.3                                           Bz 63-67                                                                              C.sub.43 H.sub.61 NO.sub.7                                                                       N.O.                               __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 56 3-(Octadecyloxy)-5-(3-phenoxypropoxy)benzenamine

A mixture of 10.9 g of3-(octadecyloxy)-5-(3-phenoxypropoxy)phenylcarbamic acid phenylmethylester and 1.2 g of 10% palladium on carbon in 200 ml of THF and 50 ml ofethyl acetate was stirred under a hydrogen atmosphere at roomtemperature for 17 hours. The catalyst was removed by filtration and thefiltrate was concentrated to a solid which was recrystallized from ethylacetate-hexane to give 8.0 g (92% yield, mp 74°-76°) of3-(octadecyloxy)-5-(3-phenoxypropoxy)benzenamine. The structure wasconfirmed by nmr and mass spectra.

The compounds in Table 17 were prepared using the procedure of Example56 if the precursor was a benzyl ester or the procedure of Example 91 ifthe precursor was a t-butylester.

                                      TABLE 17                                    __________________________________________________________________________     ##STR45##                                                                                                  Microanalytical Data                                                          Calcd    Found                                  Ex.                                                                              R              mp (°C.)                                                                    E.F.   C  H  N  C  H   N                               __________________________________________________________________________    56a                                                                              (CH.sub.2).sub.2 OAc                                                                         79-80                                                                              C.sub.20 H.sub.49 NO.sub.4                                                                       N.O.                                56b                                                                              CH.sub.2 COOCH.sub.3                                                                         69-71                                                                              C.sub.27 H.sub.47 NO.sub.4                                                                       N.O.                                56c                                                                              (CH.sub.2).sub.10 COOCH.sub.3                                                                44-45                                                                              C.sub.36 H.sub.65 NO.sub.4                                                           75.03                                                                            11.38                                                                            2.43                                                                             75.31                                                                            11.31                                                                             2.28                            56d                                                                              CO-1-Adamantyl 80-81                                                                              C.sub.35 H.sub.57 NO.sub.3                                                           77.87                                                                            10.64                                                                            2.59                                                                             77.17                                                                            10.47                                                                             2.46                            56e                                                                              COCH(C.sub.6 H.sub.5).sub.2                                                                  62-63                                                                              C.sub.38 H.sub.53 NO.sub.3                                                           79.82                                                                            9.34                                                                             2.45                                                                             79.98                                                                            9.56                                                                              2.33                            56f                                                                              (CH.sub.2).sub.2 O-2-Naphthyl                                                                100-102                                                                            C.sub.36 H.sub.53 NO.sub.3                                                           78.93                                                                            9.75                                                                             2.56                                                                             78.71                                                                            9.77                                                                              2.50                            56g                                                                              (CH.sub.2).sub. 3 O-3-Pyridyl                                                                64-68                                                                              C.sub.32 H.sub.52 N.sub.2 O.sub.3                                                    74.96                                                                            10.22                                                                            5.46                                                                             74.80                                                                            10.27                                                                             5.38                            56h                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-OCH.sub.3                                               52-53                                                                              C.sub.34 H.sub.55 NO.sub.4                                                           75.37                                                                            10.23                                                                            2.59                                                                             75.22                                                                            10.51                                                                             2.50                            56i                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OCH.sub.3                                               64-66                                                                              C.sub.34 H.sub.55 NO.sub.4                                                           75.37                                                                            10.23                                                                            2.59                                                                             75.43                                                                            10.26                                                                             2.57                            56j                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OBz                                                     80-82                                                                              C.sub.40 H.sub.59 NO.sub.4                                                                       N.O.                                56k                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-NO.sub.2                                                81-83                                                                              C.sub.33 H.sub.52 N.sub.2 O.sub.5                                                                N.O.                                56l                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-COOCH.sub.3                                             78-79                                                                              C.sub.35 H.sub.55 NO.sub.5                                                           73.77                                                                            9.73                                                                             2.46                                                                             73.15                                                                            9.76                                                                              2.32                            56m                                                                              (CH.sub.2).sub.2 O(CH.sub.2).sub.2 O(CH.sub.2).sub.2 OC.sub.2 H.sub.5                        oil  C.sub.32 H.sub.59 NO.sub.5                                                                       N.O.                                __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 57N[3-(Octadecyloxy)-5-(3-phenoxypropoxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]-glycinephenylmethyl ester

A mixture d 8.0 g (0.016 mol) of3-(octadecyloxy)-5-(3-phenoxypropoxy)benzenamine, 25 ml (0.157 mol) ofbenzylbromoacetate, 8.4 g (0.04 mol) of 1,8-bis(dimethylamino)naphthaleneand 1.2 g (0.008 mol) of sodium iodide in 400 ml ofacetonitrile was heatedat reflux for 48 hours. The solvent was removedat reduced pressure and theresidue was dissolved in ethyl acetate. Theextract was washed with 0.05N HCl, with NaHCO₃ solution, dried andconcentrated to an oil which waspurified by HPLC using 12.5% ethylacetate-hexane to give 7.4 g (59% yield,mp 59°-61°) ofN-[3-(octadecyloxy)-5-(3-phenoxypropoxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester. The structure was confirmed by nmr and mass spectra.

The compounds in Table 18 were prepared by the procedure of Example 57using benzyl bromoacetate or methyl bromoacetate.

                                      TABLE 18                                    __________________________________________________________________________     ##STR46##                                                                                                     Microanalytical Data                                                          Calcd    Found                               Ex.                                                                              R              R' mp (°C.)                                                                    E.F.   C  H  N  C  H    N                           __________________________________________________________________________    57a                                                                              (CH.sub.2).sub.2 OAc                                                                         CH.sub.3                                                                         64-66                                                                              C.sub.34 H.sub.57 NO.sub.8                                                                       N.O.*                            57b                                                                              (CH.sub.2)COOCH.sub.3                                                                        Bz 72-74                                                                              C.sub.45 H.sub.63 NO.sub.8                                                           72.45                                                                            8.51                                                                             1.88                                                                             72.21                                                                            8.83 1.95                        57c                                                                              (CH.sub.2).sub.4 COOCH.sub.3                                                                 Bz 48-50                                                                              C.sub.48 H.sub.69 NO.sub.8                                                                       N.O                              57d                                                                              CO-1-Adamantyl Bz oil  C.sub.53 H.sub.73 NO.sub.7                                                                       N.O.                             57e                                                                              COCH(C.sub.6 H.sub.5).sub.2                                                                  Bz oil  C.sub.56 H.sub.59 NO.sub.7                                                                       N.O.                             57f                                                                              (CH.sub.2).sub.2 O-2-Naphthyl                                                                Bz 68-71                                                                              C.sub.54 H.sub.69 NO.sub. 7                                                          76.83                                                                            8.24                                                                             1.66                                                                             76.78                                                                            8.36 1.56                        57g                                                                              (CH.sub.2).sub.3 O-3-Pyridyl                                                                 Bz oil  C.sub.50 H.sub.68 N.sub.2 O.sub.7                                                                N.O.                             57h                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-OCH.sub.3                                               Bz 58-61                                                                              C.sub.52 H.sub.71 NO.sub.8                                                           74.52                                                                            8.54                                                                             1.67                                                                             74.30                                                                            8.41 1.74                        57i                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OCH.sub.3                                               Bz 50-52                                                                              C.sub.52 H.sub.71 NO.sub.8                                                                       N.O.                             57j                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OBz                                                     Bz 59-61                                                                              C.sub.58 H.sub.75 NO.sub.8                                                                       N.O.                             57k                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-NO.sub.2                                                CH.sub.3                                                                         70-71                                                                              C.sub.39 H.sub.60 N.sub.2 O.sub.9                                                                N.O.                             57l                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-COOCH.sub.3                                             Bz 75-78                                                                              C.sub.53 H.sub.71 NO.sub.9                                                           73.50                                                                            8.26                                                                             1.62                                                                             73.81                                                                            8.44 1.73                        57m                                                                              (CH.sub.2).sub.2 O(CH.sub.2).sub.2 O(CH.sub.2).sub.2 OC.sub.2 H.sub.5                        CH.sub.3                                                                         oil  C.sub.38 H.sub.67 NO.sub.9                                                           66.93                                                                            9.90                                                                             2.05                                                                             66.76                                                                            10.20                                                                              1.97                        __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 58N-(Carboxymethyl)-N-[3-(octadecyloxy)-5-(3-phenoxypropoxy)phenyl]glycine

A mixture of 7.4 g ofN-[3-(octadecyloxy)-5-(3-phenoxypropoxy)phenyl]-N-2-(phenylmethoxy)-2-oxoethyl]glycinephenylmethyl ester and 1.8 g of 10% palladium on carbon in 100ml of THFand 100 ml of ethyl acetate was shaken under a hydrogen atmosphere atroom temperature for 3.5 hours. The catalyst was removed by filtrationand the filtrate was concentrated at reduced pressure to a solid whichwas triturated with ether-hexane and filtered to give 5.35 g (93% yield,mp 99°-102°) ofN-(carboxymethyl)-N-[3-(octadecyloxy)-5-(3-phenoxypropoxy)phenyl]glycine.

Anal. Calcd for C₃₇ H₅₇ NO₇ : C, 70.78; H, 9.15; N, 2.23. Found: C,70.93; H, 9.30; N, 2.24.

The compounds in Table 19 were prepared using the procedure of Example58, if the precursor was a benzyl ester, or base hydrolysis using sodiumhydroxide if the precursor was a methyl ester.

                                      TABLE 19                                    __________________________________________________________________________     ##STR47##                                                                                                Microanalytical Data                                                          Calcd    Found                                    Ex.                                                                              R            mp (°C.)                                                                    E.F.   C  H  N  C  H    N                                __________________________________________________________________________    58a                                                                              (CH.sub.2).sub.2 OH                                                                        136-138                                                                            C.sub.30 H.sub.51 NO.sub.7                                                           67.01                                                                            9.57                                                                             2.60                                                                             67.32                                                                            9.23 2.58                             58b                                                                              CH.sub.2 COOCH.sub.3                                                                       110-113                                                                            C.sub.31 H.sub.51 NO.sub.8                                                           65.81                                                                            9.09                                                                             2.48                                                                             65.48                                                                            8.73 2.44                             58c                                                                              CH.sub.2 COOH                                                                              160-190                                                                            C.sub.30 H.sub.49 NO.sub.8                                                           65.31                                                                            8.95                                                                             2.54                                                                             64.96                                                                            8.67 2.55                             58d                                                                              (CH.sub.2).sub.10 COOCH.sub.3                                                              42-45                                                                              C.sub.40 H.sub.69 NO.sub.8                                                                        N.O.*                                58e                                                                              (CH.sub.2).sub.10 COOH                                                                     43-45                                                                              C.sub.39 H.sub.67 NO.sub.8                                                                       N.O.                                  58f                                                                              CO-1-Adamantyl                                                                             foam C.sub.39 H.sub.61 NO.sub.7                                                                       N.O.                                  58g                                                                              COCH(C.sub.6 H.sub.5).sub. 2                                                               105-108                                                                            C.sub.42 H.sub.57 NO.sub.7                                                                       N.O.                                  58h                                                                              (CH.sub.2).sub.2 O-2-Naphthyl                                                              126-129                                                                            C.sub.40 H.sub.57 NO.sub.7                                                           72.37                                                                            8.65                                                                             2.11                                                                             71.62                                                                            8.65 2.01                             58i                                                                              (CH.sub.2).sub.3 O-3-Pyridyl                                                               118-121                                                                            C.sub.36 H.sub.56 N.sub.2 O.sub.7                                                    68.76                                                                            8.98                                                                             4.45                                                                             67.05                                                                            8.91 4.31                             58j                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-OCH.sub.3                                             78-82                                                                              C.sub.38 H.sub.59 NO.sub.8                                                           69.38                                                                            9.04                                                                             2.13                                                                             69.38                                                                            9.24 2.05                             58k                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OCH.sub.3                                             127-129                                                                            C.sub.38 H.sub.59 NO.sub.8                                                           69.38                                                                            9.04                                                                             2.13                                                                             69.09                                                                            8.91 2.09                             58l                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-OH                                                    142-144                                                                            C.sub.37 H.sub.57 NO.sub.8                                                           69.02                                                                            8.92                                                                             2.18                                                                             68.78                                                                            8.74 2.13                             58m                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-NO.sub.2                                              87-89                                                                              C.sub.37 H.sub.56 N.sub.2 O.sub.9                                                    65.61                                                                            8.41                                                                             4.14                                                                             65.54                                                                            8.35 4.13                                                  0.25 H.sub.2 O                                                                       H.sub.2 O                                                                        0.66  H.sub.2 O                                                                        0.52                                  58n                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -3-NH.sub.2                                              155-157                                                                            C.sub.37 H.sub.58 N.sub.2 O.sub.7                                                    69.13                                                                            9.09                                                                             4.36                                                                             68.60                                                                            9.31 4.19                             58o                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-COOCH.sub.3                                           143-146                                                                            C.sub.39 H.sub.59 NO.sub.9                                                           68.29                                                                            8.67                                                                             2.04                                                                             68.00                                                                            8.91 1.92                             58p                                                                              (CH.sub.2).sub.3 OC.sub.6 H.sub.4 -4-COOH                                                  135-136                                                                            C.sub.38 H.sub.57 NO.sub.9                                                           67.93                                                                            8.55                                                                             2.08                                                                             68.00                                                                            8.62 1.97                             __________________________________________________________________________    *Not obtained                                                             

EXAMPLE 59 3-(Octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]benzoic acidphenylmethyl ester

A mixture of 10.0 g (0.02 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acidphenylmethyl ester, 4.3 ml (0.03 mol) of methyl 5-bromovalerate, 5.6 g(0.04 mol) of potassium carbonate and 3.0 g (0.02 mol) of sodium iodidein300 ml of acetone and 75 ml of DMF was stirred at reflux under argonfor 40hours. The reaction mixture was filtered and the filtrate wasconcentrated at reduced pressure to a solid which was recrystallizedfrom methylene chloride-methanol to give 11.3 g (92% yield, mp 40°-42°)of 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]benzoic acidphenylmethyl ester. The structure was confirmed by nmr and mass spectra.

EXAMPLE 60 3-(Octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]benzoic acid

A mixture of 11.3 g of3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]benzoic acid phenylmethylester and 1.5 g of 10% palladium on carbon in 250 ml of THF was stirredina hydrogen atmosphere at room temperature for 4 hours. The catalystwas removed by filtration and the filtrate was concentrated at reducedpressure to a solid which was triturated with hexane and filtered togive 9.37 g (98% yield, mp 68°-70°) of3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl) oxy]benzoic acid.

Anal. Calcd for C₃₁ H₅₂ O₆ : C, 71.50; H, 10.07. Found: C, 71.71; H,10.21.

EXAMPLE 61 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenylcarbamicacid phenylmethyl ester

To a stirred solution of 9.37 g (0.018 mol) of3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl) oxy]benzoic acid in 200 mlof anhydrous toluene stirred with ice bath cooling under an argonatmosphere was added 4.7 ml (0.021 mol) of diphenylphosphoryl azidefollowed by 3.0 ml (0.021 mol) of triethylamine added dropwise over 15minutes. The reaction mixture was stirred in the ice bath for 2 hoursand then was heated at 90° for 2 hours. Benzyl alcohol (65 ml) was addedand heating at 90° was continued for 4 hours. The solvent and excessbenzyl alcohol were removed at reduced pressure and the residue wasdissolved in ethyl acetate. The extract was washed with NaHCO₃ solution,dried and concentrated at reduced pressure to a solid. Purification bychromatography on 150 g of silica gel using methylene chloride gave 8.9g (79% yield, mp 59°-62°) of 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenylcarbamic acid phenylmethyl ester. Thestructure was confirmed by the nmr spectrum.

EXAMPLE 62 5-[3-Amino-5-(octadecyloxy)phenoxy]pentanoic acid methylester

A mixture of 8.9 g of3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenylcarbamic acidphenylmethyl ester and 1.5 g of 10% palladium on carbon in 250 ml of THFwas stirred in a hydrogen atmosphere at room temperature for 2.5 hours.The catalyst was removed by filtration and the filtrate was concentratedat reduced pressure to a solid which was triturated with hexane andfiltered to give 6.8 g (97% yield, mp 57°-59°) of5-[3-amino-5-(octadecyloxy) phenoxy]pentanoic acid methyl ester.

Anal. Calcd for C₃₀ H₅₃ NO₄ : C, 73.27; H, 10.86; N, 2.85. Found: C,72.86; H, 10.77; N, 2.95.

EXAMPLE 63N-[3-(Octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester

A mixture of 6.77 g (13.8 mmol) of5-[3-amino-5-(octadecyloxy)phenoxy]pentanoic acid methyl ester, 6.6 ml(41.3 mmol) of benzyl bromoacetate, 7.4 g (34.4 mmol) of1,8-bis(dimethylamino)naphthalene and 0.6 g (3.9 mmol) of sodium iodidein150 ml of acetonitrile and 50 ml of DMF was stirred at reflux under anargon atmosphere for 48 hours. The reaction mixture was concentrated atreduced pressure to remove the solvents and ethyl acetate was added totheresidue. The extract was washed with 0.5N HCl, with NaHCO₃ solution,dried and concentrated at reduced pressure to an oil. Purification byHPLCusing 20% ethyl acetate-hexane gave 6.55 g (60% yield, mp 48°-50°)ofN-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester.

Anal. Calcd for C₄₈ H₆₉ NO₈ : C, 73.16; H, 8.83; N, 1.78. C,73.02; H,8.91; N, 1.75.

EXAMPLE 64N-(Carboxymethyl)-N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]glycine

A mixture of 6.5 g ofN-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycinephenylmethyl ester and 1.5 g of 10% palladium on carbon in 200 ml of THFwas stirred in a hydrogen atmosphere at room temperature for 2.5 hours.The catalyst was removed by filtration and the filtrate was concentratedat reduced pressure to a solid which was triturated with hexane.Filtration gave 4.73 g (94% yield, mp 91°-94°) ofN-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]glycine.

Anal. Calcd for C₃₅ H₅₇ NO₈ : C, 67.19; H, 9.45; N, 2.30. Found: C,67.02; H, 9.41; N, 2.19.

EXAMPLE 65N-[3-(4-Carboxybutoxy)-5-octadecyloxy)phenyl]-N-(carboxymethyl)glycine

A solution of 2.0 g (3.3 mmol) ofN-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]glycineand 2.8 ml (16.5 mmol) of 6N NaOH in 100 ml of methanol was stirred atreflux under argon for 16 hours. After cooling to room temperature, theprecipitated sodium salt was removed by filtration, dissolved in 300 mlof water and the mixture was acidified with 4 ml of 6NHCl. The productwas extracted with ethyl acetate and the dried extract wasconcentratedat reduced pressure to a solid which was recrystallized fromacetone-hexane to give 1.8 g (92% yield, mp 126°-128°) ofN-[3-(4-carboxybutoxy)-5-(octadecyloxy)phenyl]-N-(carboxymethyl)glycine.

Anal. Calcd for C₃₃ H₅₅ NO₈ : C, 66.75; H,. 9.34; N, 2.36. Found: C,66.90; H, 9.61; N, 2.33.

EXAMPLE 66 3-Nitro-5-(octadecyloxy)benzoic acid methyl ester

A mixture of 1.7 g (8.6 mmol) of 3-hydroxy-5-nitrobenzoic acid methylester [prepared as described by D. J. Abraham, D. M. Gazze, P. E.Kennedy and M.Mokotoff, J. Med. Chem. 27, 1549 (1984)], 3.2 g (9.5 mmol)of 1-bromooctadecane and 1.8 g (12.9 mmol) of potassium carbonate in 35ml ofanhydrous DMF was stirred and heated at 75° for 25 hours. Aftercooling, 150 ml of methylene chloride was added and the insoluble saltswere removed by filtration. The filtrate was concentrated at reducedpressure to a solid which was purified by HPLC using 30% methylenechloride-hexane to give 3.57 g (92% yield, mp 64°-66°) of3-nitro-5-(octadecyloxy) benzoic acid methyl ester.

Anal. Calcd for C₂₆ H₄₃ NO₅ : C, 69.45; H, 9.64; N, 3.12. Found: C,69.39; H, 9.66; N, 3.04.

The compounds in Table 20 were prepared using the procedure of Example66.

                                      TABLE 20                                    __________________________________________________________________________     ##STR48##                                                                                          Microanalytical Data                                                          Calcd Found                                             Ex.                                                                              R   R'  mp (°C.)                                                                    E.F.  C H N C  H  N                                           __________________________________________________________________________    66a                                                                              C.sub.14 H.sub.29                                                                 OCH.sub.3                                                                         50-53                                                                              C.sub.22 H.sub.35 NO.sub.5                                                                N.O.                                              66b                                                                              C.sub.10 H.sub.21                                                                 OCH.sub.3                                                                         42-44                                                                              C.sub.18 H.sub.27 NO.sub.5                                                                N.O.                                              __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 67 3-Amino-5-(octadecyloxy)benzoic acid methyl ester

A mixture of 3.55 g of 3-nitro-5-(octadecyloxy)benzoic acid methyl esterand 0.75 g of 10% palladium on carbon in 100 ml of THF was shaken underaninitial hydrogen pressure of 52 psi until uptake ceased after 1.5hours. The catalyst was removed by filtration and the filtrate wasconcentrated at reduced pressure to give 3.28 g of pure3-amino-5-(octadecyloxy)benzoicacid methyl ester.

Anal. Calcd for C₂₆ H₄₅ NO₃ : C, 74.43; H, 10.81; N, 3.34. Found: C,74.10; H, 10.90; N, 3.04.

The compounds in Table 21 were prepared using the procedure of Example67.

                                      TABLE 21                                    __________________________________________________________________________     ##STR49##                                                                                          Microanalytical Data                                                          Calcd Found                                             Ex.                                                                              R   R'  mp (°C.)                                                                    E.F.  C H N C  H  N                                           __________________________________________________________________________    67a                                                                              C.sub.14 H.sub.29                                                                 OCH.sub.3                                                                         84-87                                                                              C.sub.22 H.sub.37 NO.sub.3                                                                   N.O.                                           67b                                                                              C.sub.10 H.sub.21                                                                 OCH.sub.3                                                                         77-79                                                                              C.sub.18 H.sub.29 NO.sub.3                                                                   N.O.                                           __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 68N-[3-(Methoxycarbonyl)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester

A mixture of 3.25 g (7.74 mmol) of 3-amino-5-(octadecyloxy)benzoic acidmethyl ester, 3.7 ml (23 mmol) of benzyl bromoacetate, 4.2 g (19.4 mmol)of 1,8-bis(dimethylamino)naphthalene and 0.3 g (2.2 mmol) of sodiumiodidein 65 ml of acetonitrile and 20 ml of DMF was stirred and heatedat reflux under argon for 48 hours. The reaction mixture wasconcentrated at reducedpressure and ethyl acetate was added to theresidue. The extract was washedwith 0.05N HCl, with saturated NaHCO₃solution, dried and concentratedat reduced pressure to a solid which waspurified by HPLC using 15% ethyl acetate-hexane to give 2.6 g (48%yield, mp 62°-63°) ofN-[3-(methoxycarbonyl)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester.

Anal. Calcd for C₄₄ H₆₁ NO₇ : C, 73.81; H, 8.59; N, 1.96. Found: C,73.46; H, 8.69; N, 2.01.

The compounds in Table 22 were prepared using the procedure of Example68.

                                      TABLE 22                                    __________________________________________________________________________     ##STR50##                                                                                          Microanalytical Data                                                          Calcd Found                                             Ex.                                                                              R   R'  mp (°C.)                                                                    E.F.  C H N C  H   N                                          __________________________________________________________________________    68a                                                                              C.sub.14 H.sub.29                                                                 OCH.sub.3                                                                         52-54                                                                              C.sub.40 H.sub.53 NO.sub.7                                                                   *N.O.                                          68b                                                                              C.sub.10 H.sub.21                                                                 OCH.sub.3                                                                         oil  C.sub.36 H.sub.45 NO.sub.7                                                                   N.O.                                           __________________________________________________________________________    *Not Obtained                                                             

EXAMPLE 69N-(Carboxymethyl)-N-[3-(methoxycarbonyl)-5-(octadecyloxy)phenyl]glycine

A mixture of 2.63 g (3.67 mmol) ofN-[3-(methoxycarbonyl)-5-(octadecyloxy)phenyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycinephenylmethyl ester and 0.5 g of 10% palladium on carbon in 150ml of THFwas shaken in a hydrogen atmosphere at room temperature for 3 hours. Thecatalyst was removed by filtration and the filtrate was concentrated toa solid which was recrystallized from methanol-water to give 1.84 g (93%yield, mp 119°-123°) ofN-(carboxymethyl)-N-[3-(methoxy-carbonyl)-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₃₀ H₄₉ NO₇ : C, 67.26; H, 9.22; N, 2.61. Found: C,67.35; H, 9.57; N, 2.53.

Compounds 69a and c in Table 23 were prepared using the procedure ofExample 69. Compounds 69b and d were prepared by base hydrolysis of 69aand c respectively, as in Example 70.

                                      TABLE 23                                    __________________________________________________________________________     ##STR51##                                                                                            Microanalytical Data                                                          Calcd    Found                                        Ex.                                                                              R   R'    mp (°C.)                                                                    E.F.  C  H  N  C  H  N                                      __________________________________________________________________________    69a                                                                              C.sub.14 H.sub.29                                                                 COOCH.sub.3                                                                         121-124                                                                            C.sub.26 H.sub.41 NO.sub.7                                                          65.11                                                                            8.62                                                                             2.92                                                                             65.15                                                                            8.75                                                                             2.90                                   69b                                                                              C.sub.14 H.sub.29                                                                 COOH  153-156                                                                            C.sub.25 H.sub.39 NO.sub.7                                                          63.88                                                                            8.47                                                                             2.98                                                                             64.55                                                                            8.39                                                                             2.70                                                     0.25 H.sub.2 O                                                                      H.sub.2 O                                                                        0.96  H.sub.2 O                                                                        1.12                                      69c                                                                              C.sub.10 H.sub.21                                                                 COOCH.sub.3                                                                         126-128                                                                            C.sub.22 H.sub.33 NO.sub.7                                                          62.39                                                                            7.85                                                                             3.31                                                                             62.12                                                                            7.80                                                                             3.26                                   69d                                                                              C.sub.10 H.sub.21                                                                 COOH  160-162                                                                            C.sub.21 H.sub.31 NO.sub.7                                                          60.93                                                                            7.67                                                                             3.38                                                                             61.06                                                                            261                                                                              3.29                                                     0.25 H.sub.2 O                                                                      H.sub.2 O                                                                        1.09  H.sub.2 O                                                                        0.94                                      __________________________________________________________________________

EXAMPLE 70 N-[3-Carboxy-5-(octadecyloxy)phenyl]-N-(carboxymethyl)glycine

A solution of 1.0 g (1.81 mmol) ofN-(carboxymethyl)-N-[3(methoxycarbonyl)-5-(octadecyloxy)phenyl]glycineand3.1 ml (9.35 mmol) of 3N NaOH in 100 ml of methanol was stirred atreflux under argon for 48 hours. The warm solution was acidified with 3NHCl to pH 2 and the methanol was removed at reduced pressure. Water wasadded andthe product was filtered and recrystallized from methanol-waterto give 0.78 g (80% yield, mp 149°-155°) ofN-[3-carboxy-5-(octadecyloxy)phenyl]-N-(carboxymethyl)glycine as ahydratewith 0.75 mole of water.

Anal. Calcd for C₂₉ H₄₇ NO₇.0.75 H₂ O: C, 65.08; H, 9.13; N, 2.62; H₂ O,2.52. Found: C, 64.55: H, 9.01; N, 2.57; H₂O, 2.38.

EXAMPLE 71 3-Nitro-5-(octadecyloxy)benzoic acid

A solution of 4.5 g of 3-nitro-5-(octadecyloxy)benzoic acid methyl esterand 4 ml of 6N NaOH in 200 ml of methanol and 50 ml of dioxane wasstirredat reflux for 2.5 hours. The solvents were removed at reducedpressure and the residue was acidified with 1N HCl. The solid wasfiltered and recrystallized from methanol-water to give 2.7 g (62%yield, mp 101°-103°) of 3-nitro-5-(octadecyloxy)benzoic acid.

Anal. Calcd for C₂₅ H₄₁ NO₅ : C, 68.93; H, 9.49; N, 3.22. Found: C,67.94; H, 9.55; N, 3.02.

EXAMPLE 72 3-Nitro-5-(octadecyloxy)benzamide

A solution of 5.0 g of 3-nitro-5-(octadecyloxy)benzoic acid in 50 ml ofthionyl chloride was refluxed for 3 hours. The excess thionyl chloridewasremoved at reduced pressure and the resultant solid acid chloride wasdissolved in 100 ml of methylene Chloride. Ammonia gas was bubbledthroughthe solution for 10 minutes and the reaction mixture was left atroom temperature for 1 hour. The solvent was removed at reduced pressureand the solid residue was triturated with THF and the product wasremoved by filtration to give 4.75 g, mp 117°-120°, of3-nitro-5-(octadecyloxy)benzamide. The structure was confirmed by nmrand mass spectra.

EXAMPLE 73 3-Amino-5-(octadecyloxy)benzamide

A mixture of 4.75 g of 3-nitro-5-(octadecyloxy)benzamide and 1.0 g of10% palladium on carbon in 750 ml of THF was shaken in a hydrogenatmosphere at room temperature until uptake ceased after 4 hours. Thecatalyst was removed by filtration and the filtrate was concentrated atreduced pressure to a solid which was recrystallized from methanol togive 4.0 g (91% yield, mp 139°-143°) of3-amino-5-(octadecyloxy)benzamide.

Anal. Calcd for C₂₅ H₄₄ N₂ O₂ : C, 74.21; H, 10.96; N, 6.92. Found: C,74.12; H, 11.07; N, 6.81.

EXAMPLE 74N-[(3-Carbamoyl)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester

A mixture of 3.0 g (7.4 mmol) of 3-amino-5-(octadecyloxy)benzamide, 3.6ml (22 mmol) of benzyl bromoacetate, 4.0 g (18.5 mmol) of1,8-bis(dimethylamino)naphthalene and 0.3 g (2.1 mmol) of sodium iodidein60 ml of acetonitrile and 20 ml of DMF was stirred and heated atreflux under argon for 48 hours. The solvents were removed at reducedpressure and the residue was dissolved in ethyl acetate. The extract waswashed with 0.05N HCl, with NaHCO₃ solution, dried and concentrated atreduced pressure to a solid. Purification by HPLC using 20% ethylacetate-toluene gave 2.24 g (43% yield, mp 112°-114°) ofN-[(3-carbamoyl)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester.

Anal. Calcd for C₄₃ H₆₀ N₂ O₆ : C, 73.68; H, 8.63; N, 4.00. Found: C,73.69; H, 8.64; N, 3.90.

EXAMPLE 75N-(Carboxymethyl)-N-[(3-carbamoyl)-5-(octadecyloxy)phenyl]glycine

A mixture of 2.2 g ofN-[(3-carbamoyl)-5-(octadecyloxy)phenyl]-N-[2(phenylmethoxy)-2-oxoethyl]glycinephenylmethyl ester and 0.5 g of 10% palladium on carbon in 100 ml of THFwas stirred in a hydrogen atmosphere at room temperature until uptakeceased after 3 hours. DMF (150 ml) was added and the mixture was heatedtodissolve the precipitated product. The hot mixture was filtered toremove the catalyst and the filtrate was concentrated at reducedpressure to a solid. Recrystallization from THF gave 1.1 g (69% yield,mp 213°-216°) ofN-(carboxymethyl)-N-[(3-carbamoyl)-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₂₉ H₄₈ N₂ O₆ : C, 66.89; H, 9.29; N, 5.38. Found: C,66.58; H, 9.30; N, 5.19.

EXAMPLE 76 3-Acetyloxy-5-(octadecyloxy)benzenecarboxylic acid

To a stirred and ice bath cooled solution of 5.0 g (0.01 mol) of3-hydroxy-5-(octadecyloxy) benzoic acid phenylmethyl ester in 7.5 ml ofmethylene chloride and 2.8 ml (0.02 mol) of triethylamine was added 0.86ml (0.012 mol) of acetyl chloride. The reaction mixture was stirred inan ice bath for 1 hour, at room temperature for 2 hours and then waswashed with 1N HCl, with NaHCO₃ solution, dried and concentrated atreduced pressure to a solid. Trituration with methanol and filtrationgave 5.17 g (96% yield, mp 55°-56°) of3-acetyloxy-5-(octadecyloxy)benzenecarboxylic acid.

Anal. Calcd for C₂₇ H₄₄ O₅ : C, 72.28; H, 9.89. Found: C, 72.16; H,9.79.

EXAMPLE 77 3-Acetyloxy-5-(octadecyloxy)phenylcarbamic acid phenylmethylester

To a solution of 3.0 g (6.7 mmol) of3-acetyloxy-5-(octadecyloxy)benzenecarboxylic acid in 70 ml of drytolueneand 10 ml of dry DMF cooled in an ice bath was added 1.7 ml (8mmol) of diphenylphosphoryl azide followed by 1.1 ml (8 mmol) oftriethylamine. Thereaction mixture was stirred in the ice bath for 1.5hours and then was heated at 90° for 5 hours. Benzyl alcohol (20 ml) wasadded and heating at 90° was continued for 16 hours. The solvents wereremoved at reduced pressure and ethyl acetate was added to the residue.The extract was washed with NaHCO₃ solution and then cooled at -18°. Theprecipitate was removed by filtration and the filtrate was concentratedat reduced pressure to an oil which was purified by chromatography on150 g of silica gel using 25% ethyl acetate-hexane to give 1.87 g (50%yield, mp 57°-59 °) of 3-acetyloxy-5-(octadecyloxy)phenylcarbamic acidphenylmethyl ester.

Anal. Calcd for C₃₄ H₅₁ NO₅ : C, 73.74; H, 9.28; N, 2.53. Found: C,73.53; H, 9.26; N, 2.45.

EXAMPLE 78 3-Acetyloxy-5-(octadecyloxy)benzenamine

A mixture of 1.87 g of 3-acetyloxy-5-(octadecyloxy)phenylcarbamic acidphenylmethyl ester and 1 g of 10% palladium on carbon in 100 ml THF wasshaken under an initial hydrogen pressure of 53 psi until uptake ceasedafter 16 hours. The catalyst was removed by filtration and the filtratewas concentrated at reduced pressure to give 1.26 g, mp 73°-74°, of pure3-acetyloxy-5-(octadecyloxy)benzenamine.

Anal. Calcd for C₂₆ H₄₅ NO₃ : C,74.42; H, 10.81; N, 3.34. Found: C,74.53; H, 10.48; N, 3.19.

EXAMPLE 79N-[3-Acetyloxy)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester

A mixture of 1.26 g (0.003 mol) of 3-acetyloxy-5-(octadecyloxy)benzeneamine, 2.4 ml (0.015 mol) of benzyl bromoacetate 2.1 g (0.01 mol) of1,8-bis(dimethylamino)naphthalene and 0.45 g (0.003 mol) of sodiumiodide in 75 mo of acetonitrile was stirred at reflux for 114 hours. Thesolvent was removed at reduced pressure and ethyl acetate was added tothe residue. The extract was washed with 1N HCl, with NaHCO₃ solution,dried and concentrated to a solid which was purified by chromatographyon 150 g of silica gel using 17% ethyl acetate to give 1.0 g, mp52°-53°, ofN-[(3-acetyloxy)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)-ethyl]glycinephenylmethyl ester. The structure was confirmed by nmr and mass spectra.

EXAMPLE 80N-[3-Acetyloxy)-5-octadecyloxy)phenyl-N-(carboxymethyl)glycine

A mixture of 1.0 g ofN-[(3-acetyloxy)-5-(octadecyloxy)phenyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycinephenylmethyl ester and 0.5 g of 10% palladium on carbon in 40 ml ofethyl acetate was shaken under an initial hydrogen pressure of 50 psiuntil uptake ceased after 2.5 hours. The mixture was heated to boilingandfiltered hot to remove the catalyst from the precipitated product.The filtrate was concentrated at reduced pressure to give pureN-[3-(acetyloxy)-5-(octadecyloxy)-phenyl-N-(carboxymethyl)glycine, mp122°-127°. The structure was confirmed by nmr and mass spectra.

EXAMPLE 81 N-(Carboxymethyl)-N-[3-hydroxy-5-(octadecyloxy)phenyl]glycine

To solution of 1.0 g (1.87 mmol) ofN-[3-(acetyloxy)-5-(octadecyloxy)phenyl-N-(carboxymethyl)glycine in 30ml of dioxane and 70 ml of methanol was added 1.6 ml (9.6 mmol) of 6NNaOH. The solution was kept at room temperature for 60 hours. Thesolvent was removed at reduced pressure and the residue was acidifiedwith 3N HCl. Theresultant solid was filtered to give 0.546 g, mp143°-146°, of pure N-(carboxymethyl)-N-[3-hydroxy-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₂₈ H₄₇ NO₆ : C, 68.12; H, 9.60; N, 2.84. Found: C,67.96; H, 9.86; N, 2.34.

EXAMPLE 82 3-(3-Bromopropoxy)-5-(octadecyloxy)benzoic acid phenylmethylester

A mixture of 5.0 g (0.01 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acidphenylmethyl ester, 10.2 ml (0.1 mol) of 1,3-dibromopropane and 7.0 g(0.05 mol) of potassium carbonate in 75 ml of acetone and 15 ml of DMFwasstirred at reflux for 22 hours. The reaction mixture was filtered andthe filtrate was concentrated at reduced pressure to an oil.Purification by HPLC using 5% ethyl acetate-hexane gave 4.91 g (79%yield, mp 57°-58°) of 3-(3-bromopropoxy)-5-(octadecyloxy)benzoic acidphenylmethyl ester. The structure was confirmed by the nmr spectrum.

EXAMPLE 833-[3-(Octadecyloxy)-5-(phenylmethoxycarbonyl)phenoxy]propylphosphonicacid diethyl ester

A mixture of 4.91 g (7.95 mmol) of3-(3-bromopropoxy)-5-(octadecyloxy)benzoic acid phenylmethyl ester and1.5ml (8.74 mmol) of triethyl phosphite was stirred and heated at 150°for 32 horns. Purification by chromatography on 250 g of silica gel gave3.2 g (60% yield) of3-[3-(octadecyloxy)-5-(phenylmethoxycarbonyl)phenoxy]propylphosphonicaciddiethyl ester as an oil. The structure was confirmed by the nmrspectrum.

EXAMPLE 84 3-[3-Carboxy-5-(octadecyloxy)phenoxy]propylphosphonic aciddiethyl ester

A mixture of 3.2 g of3-[3-(octadecyloxy)-5-(phenylmethoxycarbonyl)phenoxy]propylphosphonicaciddiethyl ester and 0.5 g of 10% palladium on carbon in 100 ml of THFwas stirred in a hydrogen atmosphere at room temperature for 2 hours.The catalyst was removed by filtration and the filtrate was concentratedat reduced pressure to give 2.65 g, mp 53°-55°, of3-[3-carboxy-5-(octadecyloxy)phenoxy]propylphosphonic acid diethylester.

Anal. Calcd for C₃₂ H₅₇ O₇ P: C, 65.73; H, 9.82; P, 5.30. Found: C,65.85; H, 9.77, P, 5.18.

EXAMPLE 85[3-[3-(Diethoxyphosphinyl)propoxy]-5-(octadecyloxy)phenyl]carbamic acidphenylmethyl ester

To 2.55 g (4.36 mmol) of3-[3-carboxy-5-(octadecyloxy)phenoxy]propylphosphonic acid diethyl esterin 75 ml of toluene stirred and cooled in an ice bath was added 1.12 ml(5.23 mmol) of diphenylphosphoryl azide followed by 0.73 ml (5.23 mmol)oftriethylamine added dropwise. After stirring in the ice bath for 2hours, the reaction mixture was stirred and heated at 90° for 2 hours.Benzyl alcohol (16 ml) was added and heating at 90° was continued for 4hours. The solvent and the excess benzyl alcohol were removed at reducedpressure and the residue was dissolved in ethyl acetate. The extract waswashed with NaHCO₃ solution, dried and concentrated at reduced pressureto an oil which was purified by HPLC using 50% ethyl acetate-hexane togive 2.47 g (82% yield) of[3-[3-(diethoxyphosphinyl)propoxy]-5-(octadecyloxy)-phenyl]carbamic acidphenylmethyl ester as an oil. The structure was confirmed by nmr andmass spectra.

EXAMPLE 86 [3-[3-Amino-5-(octadecyloxy)phenoxy]propyl]phosphonic aciddiethyl ester

A mixture of 2.47 g of[3-[3-(diethoxyphosphinyl)propoxy]-5-(octadecyloxy)phenyl]carbamic acidphenylmethyl ester and 0.4 g of 10% palladium on carbon in 100 ml of THFwas stirred in a hydrogen atmosphere at room temperature for 2.5 hours.The catalyst was removed by filtration and the filtrate was concentratedat reduced pressure to a solid which was recrystallized fromether-hexane to give 1.83 g (92% yield, mp 63°-65°) of[3-[3-amino-5-(octadecyloxy)phenoxy]propyl]-phosphonic acid diethylester.The structure was confirmed by nmr and mass spectra.

EXAMPLE 87N-[3-[3-(Diethoxyphosphinyl)propoxy]-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester

A mixture of 1.82 g (3.27 mmol) of[3-[3-amino-5-(octadecyloxy)phenyl]propyl]phosphonic acid diethyl ester,1.6 ml (9.82 mmol) of benzyl bromoacetate, 1.8 g (8.19 mmol) of1,8-bis(dimethylamino)naphthalene and 0.14 g (0.92 mmol) of sodiumiodide in 40 ml of acetonitrile and 15 ml of DMF was stirred at refluxunder argon for 48 hours. The reaction mixture was concentrated atreduced pressure and the residue was dissolved in ethyl acetate. Theextract was washed with 0.05N HCl, dried and concentrated at reducedpressure to an oil which was purified by HPLC using 55% ethylacetate-hexane. This gave 2.41 g (86% yield) ofN-[3-[3-(diethoxyphosphinyl)propoxy-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester as an oil. The structure was confirmed by nmr andmass spectra.

EXAMPLE 88N-Carboxymethyl)-N-[3-[3-(diethoxyphosphinyl)propoxy]-5-(octadecyloxy)phenyl]glycine

A mixture of 2.4 g ofN-[3-[3-(diethoxyphosphinyl)propoxy-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester and 0.5 g of 10% palladium on carbon in 100 ml of THFwas stirred in a hydrogen atmosphere at room temperature for 9 hours.The catalyst was removed by filtration and the filtrate was concentratedat reduced pressure to an oil which was dissolved in 25 ml of ether andcooled in an ice bath. Filtration of the solid which crystallized gave1.14 g (60% yield, mp 92°-94°)ofN-(carboxymethyl)-N-[3-[3-(diethoxyphosphinyl)propoxy-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₃₅ H₆₂ NO₉ P: C, 62.57; H, 9.30; N, 2.08; P, 4.61.Found: C, 62.66; H, 9.46; N, 2.21; P, 4.32.

EXAMPLE 89N-(Carboxymethyl)-N-[3-[3-(ethoxyphosphinyl)propoxy]-5-(octadecyloxy)phenyl]glycine

A solution of 0.226 g (0.336 mmol) ofN-(carboxymethyl)-N-[3-[3-(diethoxyphosphinyl)propoxy-5-(octadecyloxy)phenyl]glycine and 1.5 ml (1.5 mmol) of 1N NaOHin20 ml of DMSO was stirred at 100° under argon for 24 hours. Aftercooling to room temperature, the solid was removed by filtration and itwas dissolved in water and the solution was acidified with 6N HCl to pH2.Filtration gave 0.193 g (89% yield, mp 105°-108°) ofN-(carboxymethyl)-N-[3-[3-(ethoxyphosphinyl)propoxy]-5-(octadecyloxy)phenyl]glycine.The structure was confirmed by nmr and mass spectra.

EXAMPLE 90 3-Nitro-5-(octadecyloxy)phenylcarbamic acid dimethylethylester

A mixture of 5.0 g (11.5 mmol) of 3-nitro-5-(octadecyloxy)benzoic acid,3.0ml (13.8 mmol) of diphenylphosphoryl azide and 2.0 ml (13.8 mmol) oftriethylamine in 45 ml of t-butylalcohol (freshly distilled from sodium)was stirred at reflux under argon for 20 hours. The excesst-butylalcohol was removed at reduced pressure and methylene chloridewas added to the residue. The extract was washed with NaHCO₃ solution,dried and concentrated at reduced pressure to an oil which was purifiedby HPLC using 5% ethyl acetate-hexane to give 4.6 g (79% yield, mp70°-72°) of 3-nitro-5-(octadecyloxy)phenylcarbamic acid dimethylethylester. The structure was confirmed by nmr and mass spectra.

EXAMPLE 91 3-Nitro-5-(octadecyloxy)benzenamine

To a solution of 4.6 g of 3-nitro-5-(octadecyloxy)phenylcarbamic aciddimethylethyl ester in 100 ml of methylene chloride stirred at roomtemperature was added 20 ml of trifluoroacetic acid. The reactionmixture was kept at room temperature for 3.5 hours and the solvent wasthen removed at reduced pressure. The residue was treated with water andthe product was filtered and recrystallized from ethyl acetate-hexane togive 3.6 g (97% yield, mp 106°-108°) of3-nitro-5-(octadecyloxy)benzenamine.

Anal. Calcd for C₂₄ H₄₂ N₂ O₃ : C, 70.89; H, 10.41; N, 6.89. Found: C,70.79; H, 10.44; N, 6.74.

EXAMPLE 92N-(2-Methoxy-2-oxoethyl)-N-(3-nitro-5-(octadecyloxy)phenyl]glycinemethyl ester

A mixture of 2.5 g (6.1 mmol) of 3-nitro-5-(octadecyloxy)benzenamine,5.8 ml (61 mmol) of methyl bromoacetate, 3.3 g (15.4 mmol) of1,8-bis(dimethylamino)naphthalene and 0.5 g (3.3 mmol) of sodium iodidein50 ml of acetonitrile and 15 ml of DMF was stirred at reflux underargon for 32 hours. Methyl bromoacetate (3 ml), 1.5 g of1,8-bis(dimethylamino)naphthalene and 0.5 g of sodium iodide were addedand reflux was continued for 16 hours. The solvents were removed atreduced pressure and methylene chloride was added to the residue. Theextract was washed with 0.05N HCl, dried and concentrated to an oilwhich was purified by HPLC using hexane:ethyl acetate:methylene chloride(75:15:10) to give 1.44 g (43% yield, mp 68°-74°) ofN-(2-methoxy-2-oxoethyl)-N-[3-nitro-5-(octadecyloxy)phenyl]glycinemethyl ester. The structure was confirmed by nmr and mass spectra.

EXAMPLE 93 N-(Carboxymethyl)-N-[ 3-nitro-5-(octadecyloxy)phenyl]glycine

A solution of 1.44 g (2.6 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-nitro-5-(octadecyloxy) phenyl]glycinemethylester and 15 ml of 1N NaOH in 65 ml of methanol, 10 ml of dioxaneand 20 mlof water was stirred reflux for 5 hours. The solvents wereremoved at reduced pressure and the residue was dissolved in 400 ml ofhot water. After cooling to room temperature, 6N HCl was added toacidify and the resultant precipitate was filtered. Purification bychromatography on 40 gof silica gel using 20% methanol-chloroform gave1.1 g (81% yield, mp 131°-134°) of N-(carboxymethyl)-N-[3-nitro-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₂₈ H₄₆ N₂ O₇ : C, 64.34; H, 8.87; N, 5.36. Found: C,64.15; H, 8.85; N, 5.18.

EXAMPLE 94 N-(Carboxymethyl)-N-[3-amino-5-(octadecyloxy)phenyl]glycine

A mixture of 0.6 g ofN-(carboxymethyl)-N-[3-nitro-5-(octadecyloxy)phenyl]glycine and 0.2 g of10% palladium on carbon in 170 ml of THF and 10 ml of DMF was stirred inahydrogen atmosphere at room temperature until uptake ceased after 4hours. The reaction mixture was heated to dissolve the precipitatedproduct and the catalyst was removed by filtration. The filtrate wasconcentrated at reduced pressure and the solid residue was dissolved inTHF and the solution was passed through a SEP-PAK silica cartridge(Waters Associates). The eluent was concentrated at reduced pressure toa solid which was triturated with ethyl acetate and filtered to give0.25 g (44% yield, mp 185°-195°) ofN-(carboxymethyl)-N-[3-amino-5-(octadecyloxy)phenyl]glycine. Thestructurewas confirmed by nmr and mass spectra.

EXAMPLE 95 3-(Acetylamino)-5-(octadecyloxy)nitrobenzene

To a solution d 1.4 g (3.44 mmol) of 3-nitro-5-(octadecyloxy)benzenamineand 0.75 ml (5.4 mmol) of triethylamine in 85 ml of THF stirred in anice bath was added 0.25 ml (3.44 mmol) of acetyl chloride. The ice bathwas removed after 15 minutes and the reaction mixture was stirred atroom temperature for 17 hours. Triethylamine (0.3 ml) and acetylchloride (0.15ml ) were added and stirring was continued for 5 hours.The solvent was removed at reduced pressure and the residue wascrystallized from ethyl acetate-hexane to give 1.3 g (84% yield, mp103°-107°) of 3-(acetylamino)-5-(octadecyloxy)nitrobenzene. Thestructure was confirmed by nmr and mass spectra.

EXAMPLE 96 3-(Acetylamino)-5-(octadecyloxy)benzenamine

A mixture of 1.3 g of 3-(acetylamino)-5-(octadecyloxy)nitrobenzene and0.2 g of 10% palladium on carbon in 30 ml of THF and 25 ml of ethylacetate was stirred in a hydrogen atmosphere until uptake ceased after 5hours. The catalyst was removed by filtration and the filtrate wasconcentrated at reduced pressure to a solid which was recrystallizedfrom ethyl acetate-hexane to give 1.0 g, mp 115°-117°, of3-(acetylamino)-5-(octadecyloxy)benzenamine.

Anal. Calcd for C₂₆ H₄₆ N₂ O₂ : C, 74.59; H, 11.07; N, 6.69. Found: C,74.38; H, 11.17; N, 6.60.

EXAMPLE 97N-[3-(Acetylamino-5-(octadecyloxy)phenyl[-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester

A mixture of 1.1 g (2.63 mmol) of3-(acetylamino)-5-(octadecyloxy)benzenamine, 4.2 ml (26 mmol) of benzylbromoacetate, 1.4 g (6.6 mmol) of 1,8-bis-(dimethylamino)naphthalene and0.4 g (2.63 mmol) of sodium iodide in 40 ml of acetonitrile and 5 ml ofDMF was stirred at reflux for 48 hours. The solvents were removed atreduced pressure and the residue was purified by HPLC using 35% ethylacetate-hexane to give 0.3 g (16% yield, mp 89°-90°) ofN-[3-(acetylamino)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinebenzyl ester. The structure was confirmed by nmr and mass spectra.

EXAMPLE 98N-(Carboxymethyl)-N-[3-(acetylamino)-5-(octadecyloxy)phenylglycine

A mixture of 0.30 g ofN-[3-(acetylamino)-5-(octadecyloxy)phenyl]-N-2-(phenylmethoxy)-2-oxoethyl]glycinephenylmethylester and 0.10 g of 10% palladium on carbon in 15 ml ofTHF and 15 ml ofethyl acetate was stirred in a hydrogen atmosphere at roomtemperatureuntil uptake ceased after 7 hours. The catalyst was removed byfiltration and the filtrate was concentrated at reduced pressure to asolid which was recrystallized from ethyl acetate to give 0.13 g (59%yield, mp 156°-165°) ofN-(carboxymethyl)-N-[3-(acetylamino)-5-(octadecyloxy)phenylglycine.

Anal. Calcd for C₃₀ H₅₀ N₂ O₆ : C, 67.38; H, 9.42; N, 5.24. Found: C,67.28; H, 9.42; N, 5.05.

EXAMPLE 99 3-Hydroxy-5-(octadecyloxy)benzoic acid methyl ester

A mixture of 50.0 g (0.297 mol) of methyl 3,5-dihydroxybenzoate, 99.2 g(0.297 mol) of 1-bromooctadecane and 41 g (0.297 mol) of potassiumcarbonate in 1000 ml of acetone and 50 ml of DMF was stirred at refluxunder argon for 24 hours. The solvents were removed at reduced pressureand the residue was heated with methylene chloride and filtered hot. Thefiltrate was concentrated at reduced pressure to a solid which wasrecrystallized from methylene chloride-methanol to give the3,5-dialkylated product. The filtrate was concentrated to dryness andthe residue was recrystallized from methylene chloride-methanol to givemore of the dialkylated product. The filtrate was concentrated todryness and recrystallized from ether-hexane to give 40.2 g (32% yield,mp 95°-97°) of 3-hydroxy-5-(octadecyloxy)benzoic acid methyl ester.

Anal. Calcd for C₂₆ H₄₄ O₄ : C, 74.24; H, 10.54. Found: C, 73.69; H,10.57.

EXAMPLE 100 3-(Octadecyloxy)-5-(phenylmethoxy)benzoic acid methyl ester

A mixture of 50.9 g (0.12 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acidmethyl ester, 21.6 ml (0.18 mol) of benzyl bromide and 50 g (0.36 mol)of potassium carbonate in 750 ml of DMF was stirred and heated at 85°for 65 hours. The reaction mixture was filtered and the filtrate wasconcentrated at reduced pressure. The residue was recrystallized frommethylene chloride-methanol to give 46.3 g (75% yield, mp 61°-63°) of3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid methyl ester. Thestructure was confirmed by the nmr spectrum.

EXAMPLE 101 3-(Octadecyloxy)-5-(phenylmethoxy)benzoic acid

A mixture of 46.3 g (0.091 mol) of3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid methyl ester and 45 ml(0.27 mol) of 6N NaOH in 7.50 ml of methanol and 300 ml of dioxane wasstirred at reflux for 4 hours. The reaction mixture was filtered and thefiltrate was concentrated at reduced pressure. The residue was suspendedin water, acidified and filtered to give 44.4 g (99% yield, mp 97°-99°)of 3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid.

Anal. Calcd for C₃₂ H₄₈ O₄ : C, 77.38; H, 9.74. Found: C, 77.38; H,9.75.

EXAMPLE 102 3-(Octadecyloxy)-5-(phenylmethoxy)phenylcarbamic aciddimethylethyl ester

A solution of 25 g (0.05 mol) of3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid, 13 ml (0.06 mol) ofdiphenylphosphoryl azide and 8.4 ml (0.06 mol) of triethylamine in 165ml of t-butyl alcohol (freshly distilled from sodium) was stirred atreflux under argon for 19 hours. The excess t-butylalcohol was removedat reduced pressure and the residue was extracted with methylenechloride. The dried extract was concentrated to a solid which waspurified by chromatography on 200 g of 35-70 mesh silica gel using50%ethyl acetate-hexane to give 28 g of slightly impure3-(octadecyloxy)-5-(phenylmethoxy)phenylcarbamic acid dimethylethylester which was suitable for use in the next step.

EXAMPLE 103 3-(Octadecyloxy)-5-(phenylmethoxy)benzenamine

A solution of 28 g of 3-(octadecyloxy)-5-(phenylmethoxy)phenylcarbamicaciddimethylethyl ester and 76 ml of trifluoroacetic acid in 700 ml ofmethylene chloride was kept at room temperature for 2 hours. Thesolution was concentrated at reduced pressure and the residue wasextracted with methylene chloride. The extract was washed with NaHCO₃solution, dried and concentrated to a solid which was dissolved in 1000ml of ether.The solution was treated with 21 ml of 3N HCl in ethanol.The hydrochloridesalt which precipitated was filtered and treated withexcess NaHCO₃ toliberate the free base which was extracted withmethylene chloride. The dried extract was concentrated at reducedpressure to give 20.4 g (89% yield, mp 57°-59°) of3-(octadecyloxy)-5-(phenylmethoxy)benzenamine.

Anal. Calcd for C₃₁ H₄₉ NO₂ : C, 79.60; H, 10.56; N, 2.99. Found: C,79.33; H, 10.53; N, 2.98.

EXAMPLE 104N-(2-Methoxy-2-oxoethyl-N-[3-(octadecyloxy)-5-(phenylmethoxy)phenyl]glycinemethylester

A mixture of 20.3 g (0.043 mol) of3-(octadecyloxy)-5-(phenylmethoxy)benzenamine, 12 ml (0.13 mol) ofmethyl bromoacetate, 23 g (0.11 mol) of1,8-bis(dimethylamino)naphthalene and 1.8g (0.012 mol) of sodium iodidein 450 ml of acetonitrile and 150 ml of DMF was stirred at reflux underargon for 48 hours. The reaction mixture was filtered and the filtratewas concentrated at reduced pressure. The residue was extracted withethyl acetate and the extract was washed with 0.5N HCl, dried andconcentrated to a solid which was purified by HPLC using 20% ethylacetate-hexane to give 15.6 g (59% yield, mp 66°-68°) ofN-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-(phenylmethoxy)phenyl]glycinemethyl ester.

Anal. Calcd for C₃₅ H₅₇ NO₆ : C, 72.63; H, 9.39; N, 2.29. Found: C,72.60; H, 9.55; N, 2.29.

EXAMPLE 105N-[3-Hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethylester

A mixture of 15.55 g ofN-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-(phenylmethoxy)phenyl]glycine methyl ester and 3.0 g of 10% palladium on carbon in 500mlof THF was stirred in a hydrogen atmosphere at room temperature untiluptake ceased after 23 hours. The catalyst was removed by filtration andthe filtrate was concentrated at reduced pressure to a solid which wastriturated with hexane and filtered to give 12.8 g (97% yield, 96°-98°)of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester.

Anal. Calcd for C₃₀ H₅₁ NO₆ : C, 69.06; H, 9.85; N, 2.68. Found: C,69.12; H, 10.06; N, 2.72.

EXAMPLE 106 3-(3- Bromopropoxy)bromobenzene

A mixture of 5.0 g (0.029 mol) of 3-bromophenol, 29 ml (0.29 mol) of1,3-dibromopropane and 12 g (0.087 mol) of potassium carbonate in 75 mlofacetone was stirred ar reflux for 22 hours. The reaction mixture wasfiltered and the filtrate was concentrated at reduced pressure. Theresidue was purified by HPLC using 3% ethyl acetate-hexane to give 4.9 g(58% yield) of 3-(3-bromopropoxy)bromobenzene. The structure wasconfirmedby the nmr spectrum.

EXAMPLE 107N-(2-methoxy-2-oxoethyl)-N-3-3-(3-bromophenoxy)propoxy]-5(octadecyloxy)phenyl]glycinemethyl ester

A mixture of 1.0 g (1.92 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-hydroxy-5-(octadecyloxy)phenyl]glycinemethyl ester, 0.59 g (2.01 mmol) of 3-(3-bromopropoxy) bromobenzene,0.53 g (3.83 mmol) of potassium carbonate and 0.29 g (1.92 mmol) ofsodium iodide in 30 ml of acetone and 6 ml of DMF was stirred at refluxunder argon for 65 hours. The solvents were removed at reduced pressureand the residue was treated with methylene chloride and filtered. Thefiltrate wasconcentrated and crystallized from methylenechloride-methanol to give 0.99g (70%, mp 48°-50°) ofN-(2-methoxy-2-oxoethyl)-N-[3-[3-(3-bromophenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine methyl ester.

Anal. Calcd for C₃₉ H₆₀ BrNO₇ : C, 63.75; H, 8.23; N, 1.91; Br, 10.87.Found: C, 63.43; H, 8.32; N, 1.88; Br, 10.77.

EXAMPLE 108N-(Carboxymethyl)-N-3-[3-[3-(bromophenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine

A solution of 0.95 g (1.29 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-[3-(3-bromophenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine methyl ester and 0.86 ml (5.17mmol) of 6N NaOH in 20 ml of methanol and 10 ml of dioxane was stirredat reflux under argon for 4.5 hours. The solvents were removed atreduced pressure and the residue was dissolved in water and acidified topH 3 with6N HCl. The product was extracted with ethyl acetate and theextract was concentrated to dryness and the resultant solid wasreccrystallized from methanol-water to give 0.75 g (83% yield, mp93°-95°) ofN-(carboxymethyl)-N-3-[3-(3-bromophenoxy)propoxy]-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₃₇ H₅₆ BrNO₇ : C, 62.88; H, 7.99; N, 1.98; Br; 11.31.Found: C, 62.85; H, 8.08; N, 1.87; Br, 11.60.

EXAMPLE 109 3,5-Bis(phenylmethoxy)benzoic acid methyl ester

A mixture of 25.0 g (0.15 mol) of 3,5-dihydroxybenzoic acid methylester, 44 ml (0.37 mol) of benzyl bromide and 82 g (0.60 mol) ofpotassium carbonate in 300 ml of DMF was stirred and heated at 85° underargon for 45 hours. The cooled reaction mixture was filtered and thefiltrate was concentrated at reduced pressure. The residue was treatedwith methylene chloride and the extract was filtered again to removesalts. Crystallization from methylene chloride-methanol gave 41.9 g (81%yield, mp 64°-66°) of 3,5-bis(phenylmethoxy)benzoic acid methyl ester.

Anal. Calcd for C₂₂ H₂₀ O₄ : C, 75.84; H, 5.79. Found: C, 75.26; H,5.62.

EXAMPLE 110 3,5-Bis(phenylmethoxy)benzoic acid

A solution of 41.4 g (0.12 mol) of 3,5-bis(phenylmethoxy)benzoic acidmethyl ester and 59 ml (0.36 mol) of 6N NaOH in 700 ml of methanol and350ml of dioxane was stirred at reflux for 17 hours. The solvents wereremovedat reduced pressure and the residue was dissolved in water andacidified topH 3 with 6N HCl. The resultant solid was filtered andrecrystallized from methylene chloride-methanol to give 38.6 g (97%yield, mp 211°-213°) of 3,5-bis(phenylmethoxy)benzoic acid.

Anal. Calcd for C₂₁ H₁₈ O₄ : C, 75.43; H, 5.43. Found: 74.82; H, 5.34.

EXAMPLE 111 3,5-Bis(phenylmethoxy)phenyl carbamic acid dimethylethylester

A mixture of 2.0 g (5.98 mmol) of 3,5-bis(phenylmethoxy)benzoic acid,1.6 ml (7.18 mmol) of diphenylphosphoryl azide, 1.0 ml (7.18 mmol) oftriethylamine and 6 ml (64 mmol) of t-butyl alcohol (freshly distilledfrom sodium)in 15 ml of anhydrous toluene was stirred at reflux underargon for 18 hours. The reaction mixture was washed with NaHCO₃solution, dried and concentrated at reduced pressure to an oil.Chromatography on 25 g of 230-400 mesh silica gel using 10% ethylacetate-hexane gave 2.25 g (93% yield, mp 96°-98°) of3,5-bis(phenylmethoxy) phenyl carbamicacid dimethylethyl ester.

Anal. Calcd for C₂₅ H₂₇ NO₄ : C, 74.05; H, 6.71; N, 3.45. Found: C,73.69; H, 6.84; N, 3.45.

EXAMPLE 112 3,5-Bis(phenylmethoxy)benzenamine

A solution of 2.21 g of 3,5-bis(phenylmethoxy)phenyl carbamic aciddimethylethyl ester and 2.1 ml of trifluoroacetic acid in 50 ml ofmethylene chloride was left at room temperature for 18 hours. Thereactionmixture was concentrated at reduced pressure and the residue wasdissolved in methylene chloride and the extract was washed with NaHCO₃solution, dried and concentrated to an oil which was triturated withmethanol and filtered to give 0.70 g, mp 77°-80°, of3,5-bis-(phenyl-methoxy)benzenamine. The filtrate was concentrated todryness, dissolved in ether and treated with 1.6 ml of 3N HCl inethanol. The precipitated hydrochloride salt was filtered, treated withexcess NaHCO₃ solution and extracted with methylene chloride. The driedextract was concentrated to give 0.57 g more of3,5-bis(phenylmethoxy)benzenamine.

Anal. Calcd for C₂₀ H₁₉ NO₂ : C, 78.66; H, 6.27; N, 4.59. Found: C,78.47; H, 6.37; N, 4.51.

EXAMPLE 113N-(2-Methoxy-2-oxoethyl)-N-[3,5-(bis(phenylmethoxy)phenyl]glycine methylester

A mixture of 29.27 g (0.097 mol) of 3,5-bis(phenylmethoxy)benzenamine,27 ml (0.29 mol) of methyl bromoacetate, 51.7 g (0.24 mol) of1,8-bis(dimethylamino)naphthalene and 4 g (0.027 mol) of sodium iodidein 500 ml of acetonitrile and 150 ml of DMF was stirred at reflux underargonfor 48 hours. The solvents were removed at reduced pressure and theresiduewas extracted with ethyl acetate. The extract was washed with0.5N HCl, with NaHCO₃ solution, dried and concentrated to a solid.Purificationby HPLC using 4% ethyl acetate-toluene and recrystallizationfrom methylenechloride-hexane gave 28.65 g (66% yield, mp 98°-100°) ofN-(2-methoxy-2-oxoethyl)-N-[3,5-(bis(phenylmethoxy)phenyl]glycine methylester.

Anal. Calcd for C₂₆ H₂₇ NO₆ : C, 69.47; H, 6.05; N, 3.12. Found: C,69.36; H, 5.98; N; 2.73.

EXAMPLE 114 N-[(3,5-Dihydroxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester

A mixture of 28.6 g ofN-(2-methoxy-2-oxoethyl)-N-[3,5-(bis(phenylmethoxy)phenyl]glycine methylester and 5.0 g of 10% palladium on carbon in 500 ml of THF was shakenin a hydrogen atmosphere for 23 hours. The catalyst was removed byfiltrationand the filtrate was concentrated at reduced pressure to asolid which was triturated with hexane and filtered to give 16.2 g (94%yield, mp 200°-202°) ofN-[(3,5-Dihydroxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester.

Anal. Calcd for C₁₂ H₁₅ NO₆ : C, 53.53; H, 5.62; N, 5.20. Found: C,53.65; H, 5.51; N, 4.96.

EXAMPLE 115 N-(2-Methoxy-2 -oxoethyl)-N-[3,5-bis(decyloxy)phenyl]glycinemethyl ester

A mixture of 0.50 g (1.86 mmol) ofN-[(3,5-Dihydroxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester,0.81 ml (3.9 mmol) of 1-bromodecane and 0.77 g (5.57 mmol) of potassiumcarbonate in 15 ml of acetone was stirred at reflux for 24 hours. Anadditional 0.8 ml of 1-bromodecane was added and reflux was continuedfor 48 hours. The reaction mixture was filtered through a Celite pad andthe filtrate was concentrated at reduced pressure to an oil which waspurifiedby HPLC using 15% ethyl acetate-hexane to give 0.54 g (52%yield) of N-(2-methoxy-2-oxoethyl)-N-[3,5-bis-(decyloxy)phenyl]glycinemethyl ester as an oil. The nmr and mass spectra of this product wereidentical to those obtained using the procedure of Example 5.

EXAMPLE 116 3,4- Bis(tetradecyloxy)nitrobenzene

A mixture of 1.0 g (6.45 mmol) of 4-nitrocatechol, 4.8 ml (16.1 mmol) of1-bromotetradecane and 2.5 g (17.4 mmol) of potassium carbonate in 20 mlof acetone and 10 ml of DMF was stirred at reflux under argon for 24hours. The reaction mixture was filtered while hot and the filtrate wasallowed to cool to room temperature and 3.5 g (99% yield, mp 64°-66°) of3,4-bis (tetradecyloxy) nitrobenzene was obtained by filtration. Thestructure was confirmed by nmr and mass spectra.

Using this procedure, the reaction of 4-nitrocatechol with 1-bromodecanegave 3,4-bis(decyloxy)nitrobenzene (mp 60°-61°, Anal. Calcd for C₂₆ H₄₅NO₄ : C, 71.68; H, 10.41; N, 3.22. Found: C, 71.63; H, 10.55; N, 3.21.

EXAMPLE 117 3,4-Bis(tetradecyloxy)benzenamine

A mixture of 3.5 g of 3,4-bis(tetradecyloxy)nitrobenzene and 0.5 g of10% palladium on carbon in 80 ml of THF and 40 ml of ethyl acetate wasstirredin a hydrogen atmosphere for 4 hours when uptake ceased. Thecatalyst was removed by filtration and the filtrate was concentrated atreduced pressure to a solid which was recrystallized from ethylacetate-hexane to give 2.9 g (88% yield, mp 55°-58°) of 3,4-bis(tetradecyloxy)benzenamine.

Anal. Calcd for C₃₄ H₆₃ NO₂ : C, 78.85; H, 12.26; N, 2.70. Found: C,78.77; H, 12.01; N, 2.65.

The compounds in Table 24 were prepared using the procedure of Example117.

                                      TABLE 24                                    __________________________________________________________________________     ##STR52##                                                                                           Microanalytical Data                                                          Calcd    Found                                         Ex.                                                                              R       mp (°C.)                                                                    E.F.   C  H  N  C  H  N                                       __________________________________________________________________________    117a                                                                             C.sub.10 H.sub.21                                                                     41-42                                                                              C.sub.26 H.sub.47 NO.sub.2                                                           76.98                                                                            11.68                                                                            3.45                                                                             75.95                                                                            11.51                                                                            3.37                                    117b                                                                             COC.sub.13 H.sub.27                                                                   66-69                                                                              C.sub.34 H.sub.59 NO.sub.4                                                           74.81                                                                            10.89                                                                            2.57                                                                             74.95                                                                            10.70                                                                            2.63                                    117c                                                                             COC.sub.17 H.sub.35                                                                   82-84                                                                              C.sub.42 H.sub.75 NO.sub.4                                                           76.66                                                                            11.49                                                                            2.13                                                                             75.95                                                                            10.87                                                                            1.98                                    117d                                                                             CONHC.sub.18 H.sub.37                                                                 129-133                                                                            C.sub.44 H.sub.81 N.sub.3 O.sub.4                                                    73.80                                                                            11.40                                                                            5.87                                                                             73.97                                                                            11.35                                                                            5.80                                    117e                                                                             CONHC.sub.14 H.sub.29                                                                 127-131                                                                            C.sub.36 H.sub.65 N.sub.3 O.sub.4                                                    71.60                                                                            10.85                                                                            6.96                                                                             71.50                                                                            10.89                                                                            6.77                                    __________________________________________________________________________

EXAMPLE 118N-[2-oxo-2-(phenylmethoxy)ethyl]-N-[3,4-bis(tetradecyloxy)phenyl]glycinephenylmethyl ester

A mixture of 2.8 g (5.4 mmol) of 3,4-bis (tetradecyloxy)benzenamine, 8.6ml(54 mmol) of benzyl bromoacetate, 2.9 g (13.5 mmol) of1,8-bis(dimethylamino)naphthalene and 0.3 g of sodium iodide in 60 ml ofacetonitrile and 10 ml of DMF was stirred under argon for 48 hours. Thesolvents were removed at reduced pressure and the residue was treatedwithwater and extracted with ethyl acetate. The dried extract wasconcentrated and purified by HPLC using 10% ethyl acetate-hexane to give3.2 g (73% yield, mp 52°--52°) ofN-[2-oxo-2-(phenylmethoxy)ethyl]-N-[3,4-bis(tetradecyloxy)phenyl]glycinephenylmethyl ester. The structure was confirmed by nmr and mass spectra.

The compounds in Table 25 were prepared using the procedure of Example118.

                                      TABLE 25                                    __________________________________________________________________________     ##STR53##                                                                                           Microanalytical Data                                                          Calcd    Found                                         Ex.                                                                              R       mp (°C.)                                                                    E.F.   C  H  N  C  H  N                                       __________________________________________________________________________    118a                                                                             C.sub.10 H.sub.21                                                                     liquid                                                                             C.sub.44 H.sub.63 NO.sub.6                                                                       N.O.                                       118b                                                                             COC.sub.13 H.sub.27                                                                   liquid                                                                             C.sub.52 H.sub.75 NO.sub.8                                                                       N.O.                                       118c                                                                             COC.sub.17 H.sub.35                                                                   52-54                                                                              C.sub.60 H.sub.91 NO.sub.8                                                                          N.O.                                    118d                                                                             CONHC.sub.18 H.sub.37                                                                 116-119                                                                            C.sub.62 H.sub.97 N.sub.3 O.sub.8                                                                   N.O.                                    118e                                                                             CONHC.sub.14 H.sub.29                                                                 115-119                                                                            C.sub.54 H.sub.81 N.sub.3 O.sub.8                                                    72.05                                                                            9.07                                                                             4.67                                                                             71.92                                                                            9.15                                                                             4.77                                    __________________________________________________________________________

EXAMPLE 119 N-(Carboxymethyl)-N-[3,4-bis(tetradecyloxy)phenyl]glycine

A mixture ofN-[2-oxo-2-(phenylmethoxy)ethyl]-N-[3,4-bis(tetradecyloxy)phenyl]glycinephenylmethyl ester and 0.5 g of 10% palladium on carbon in 40 ml of THFand 20 ml of ethyl acetate was stirred in a hydrogen atmosphere at roomtemperature for 2.5 hours when uptake ceased. The catalyst was removedby filtration and the filtrate was concentrated at reduced pressure to asolid which was triturated with hexane and filtered to give 1.4 g (56%yield, mp 89°-93°) of pureN-(carboxymethyl)-N-[3,4-bis(tetradecyloxy)phenyl]glycine.

Anal. Calcd for C₃₈ H₆₇ NO₆ : C, 72.00; H, 10.65; N, 2.21. Found: C,71.98; H, 10.41; N, 2.08.

The compounds in Table 26 were prepared using the procedure of Example119.

                                      TABLE 26                                    __________________________________________________________________________     ##STR54##                                                                                           Microanalytical Data                                                          Calcd    Found                                         Ex R       mp (°C.)                                                                    E.F.   C  H  N  C  H   N                                      __________________________________________________________________________    119a                                                                             C.sub.10 H.sub.21                                                                     semisolid                                                                          C.sub.30 H.sub.51 NO.sub.6                                                                       N.O.                                       119b                                                                             COC.sub.13 H.sub.27                                                                   129-131                                                                            C.sub.38 H.sub.63 NO.sub.8                                                           68.95                                                                            9.59                                                                             2.12                                                                             68.96                                                                            9.58                                                                              2.13                                   119c                                                                             COC.sub.17 H.sub.35                                                                   115-120                                                                            C.sub.46 H.sub.79 NO.sub.8                                                           71.37                                                                            10.29                                                                            1.81                                                                             71.74                                                                            10.52                                                                             1.87                                   119d                                                                             CONHC.sub.18 H.sub.37                                                                 151-156                                                                            C.sub.48 H.sub.85 N.sub.3 O.sub.8                                                    69.28                                                                            10.30                                                                            5.05                                                                             69.53                                                                            10.23                                                                             5.04                                   119e                                                                             CONHC.sub.14 H.sub.29                                                                 155-159                                                                            C.sub.40 H.sub.69 N.sub.3 O.sub.8                                                    66.73                                                                            9.66                                                                             5.84                                                                             66.80                                                                            9.53                                                                              5.82                                   __________________________________________________________________________

EXAMPLE 120 3,4-Bis[(1-oxodecyl)oxy]nitrobenzene

To a stirred, ice bath cooled solution of 1.0 g (6.45 mmol) of4-nitrocatechol and 2 ml of pyridine in 25 ml of methylene chloride and5 ml of THF under argon was added 3.2 ml (15.5 mmol) of decanoylchloride in5 ml of THF. The reaction mixture was allowed to warm to roomtemperature and stirred for 18 hours when it was poured into water andextracted with methylene chloride. The dried extract was concentrated toan oil which waspurified by chromatography on 70 g of silica gel using5% ethyl acetate-hexane to give 2.9 g (97% yield, mp 45°-47°) of3,4-bis[(1-oxodecyl)oxy]nitrobenzene.

Anal. Calcd for C₂₆ H₄₁ NO₆ : C, 67.36; H, 8.91; N, 3.02. Found: C,67.47; H, 8.84; N, 2.97.

Using this procedure, the reaction of 4-nitrocatechol with tetradecanoylchloride gave 3,4-bis [(1-oxotetradecyl)oxy]nitrobenzene (mp 58°-60°,Anal. Calcd for C₃₄ H₅₇ NO₆ : C, 70.72; H, 9.98; N, 2.43. Found: C,70.91; H, 9.61; N, 2.41.

Using this procedure, the reaction of 4-nitrocatechol with octadecanoylchloride gave 3,4-bis [(1-oxooctadecyl)oxy]nitrobenzene (mp 68°-70°) Thestructure was confirmed by the nmr spectrum.

Using this procedure, the reaction of 4-nitrocatechol with octadecylisocyanate gave 3,4-bis [[(octadecylamino)carbonyl]oxy]nitrobenzene (mp117°-121°). The structure was confirmed by the nmr spectrum.

Using this procedure, the reaction of 4-nitrocatechol with tetradecylisocyanate gave 3,4-bis [[(tetradecylamino)carbonyl]oxy]nitrobenzene (mp100°-104°). The structure was confirmed by the nmr spectrum.

EXAMPLE 121 3,4-Bis[(1-oxodecyl)oxy]benzenamine

A mixture of 2.9 g of 3,4-bis[(1-oxodecyl)oxy]nitrobenzene and 0.5 g of10%palladium on carbon in 50 ml of ethyl acetate and 10 ml of THF wasstirred in a hydrogen atmosphere at room temperature for 5 hours whenuptake ceased. The catalyst was removed by filtration and the filtratewas concentrated to an oil which was crystallized from ethylacetate-hexane togive 2.5 g (92% yield, mp 44°-46°) of3,4-bis[(1-oxodecyl)oxy]benzenamine.

Anal. Calcd for C₂₆ H₄₃ NO₄ : C, 72.02; H, 10.00; N, 3.23. Found: C,72.28: H, 9.59; N, 3.25.

EXAMPLE 122N-[3,4-bis[(1-Oxodecyl)oxy]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester

A mixture of 2.5 g (5.77 mmol) of 3,4-bis[(1-oxodecyl)oxy]benzenamine,9.1 ml (57.7 mmol) of benzyl bromoacetate, 3.1 g (14.4 mmol) of1,8-bis(dimethylamino)naphthalene and 0.34 g (2.3 mmol) of sodium iodidein 50 ml of acetonitrile and 10 ml of DMF was stirred at reflux for 48hours. The solvents were removed at reduced pressure and the residue wastreated with methylene chloride and water. The organic phase wasseparated, dried and concentrated to an oil which was purified by HPLCusing 20% ethyl acetate-hexane to give 2.2 g (52% yield) ofN-[3,4-bis[(1-oxodecyl)oxy]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethylester as an oil. The structure was confirmed by nmr and mass spectra.

EXAMPLE 123 N-(Carboxymethyl)-N-[3,4-bis[(1-oxodecyl)oxy]phenyl]glycine

A mixture of 2.2 g ofN-[3,4-bis[(1-oxodecyl)oxy]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethylester and 0.5 g of 10% palladium on carbon in 20 ml of ethyl acetate and30 ml of THF was stirred in a hydrogen atmosphere at room temperatureuntil uptake ceased after 10 hours. The catalyst was removed byfiltration and the filtrate was concentrated at reduced pressure to asemisolid which was crystallized from ethyl acetate-hexane to give 1.3 g(78% yield, mp 131°-133°) ofN-(carboxymethyl)-N-[3,4-bis[(1-oxodecyl)oxy]phenyl]glycine.

Anal. Calcd for C₃₀ H₄₇ NO₈ : C, 65.55; H, 8.62; N, 2.55. Found: C,65.46; H, 8.43; N, 2.49.

EXAMPLE 124 N-[3-(Octadecyloxy)phenyl]glycine phenylmethyl ester

A mixture of 1.08 g (3.0 mmol) of 3-(octadecyloxy)benzenamine, 0.52 ml(3.3mmol) of benzyl bromoacetate and 0.8 g (6.0 mmol) of potassiumcarbonate in40 ml of acetone was stirred at reflux under argon for 18hours. The reaction mixture was filtered and the filtrate wasconcentrated at reducedpressure to an oil which was purified bychromatography on 150 g of silica gel using 20% ethyl acetate-hexane togive 1.1 g (72% yield, mp 55°-60°) of N-[3-(octadecyloxy) phenyl]glycinephenylmethyl ester.

Anal. Calcd for C₃₃ H₅₁ NO₃ : C, 77.75; H, 10.08; N, 2.75. Found: C,77.98; H, 10.09; N, 2.79.

The compounds in Table 27 were prepared using the procedure of Example124.

                                      TABLE 27                                    __________________________________________________________________________     ##STR55##                                                                                                      Microanalytical Data                                                          Calcd    Found                              Ex.                                                                              R         X        mp (°C.)                                                                    E.F.   C  H  N  C  H   N                           __________________________________________________________________________    124a                                                                             CONHC.sub.10 H.sub.21                                                                   (CH.sub.2).sub.2 COOC.sub.2 H.sub.5                                                    81-83                                                                              C.sub.33 H.sub.57 N.sub.3 O.sub.4                                                    70.80                                                                            10.26                                                                            7.51                                                                             70.73                                                                            9.99                                                                              7.41                        124b                                                                             CONHC.sub.10 H.sub.21                                                                   (CH.sub.2).sub.3 COOC.sub.2 H.sub.5                                                    102-104                                                                            C.sub.34 H.sub.54 N.sub.3 O.sub.4                                                    71.16                                                                            10.36                                                                            7.32                                                                             71.02                                                                            10.21                                                                             7.14                        124c                                                                             OC.sub.14 H.sub.29                                                                      CH.sub.2 COOBz                                                                         44-45                                                                              C.sub.43 H.sub.71 NO.sub.4                                                                       N.O.                            124d                                                                             OCH.sub.2 CHOHC.sub.8 H.sub.17                                                          CH.sub.2 COOCH.sub.3                                                                   oil  C.sub.33 H.sub.55 NO.sub.8                                                           66.75                                                                            9.34                                                                             2.36                                                                             66.82                                                                            9.19                                                                              2.37                        124e                                                                             COOC.sub.14 H.sub.29                                                                    CH.sub.2 COOBz                                                                         oil  C.sub.45 H.sub.71 NO.sub.6                                                                        N.O.                           __________________________________________________________________________

EXAMPLE 125 N-[3-(Octadecyloxy)phenyl]glycine

A mixture of 0.52 g of N-[3-(octadecyloxy)phenyl]glycine phenylmethylesterand 0.2 g of 10% palladium on carbon in 40 ml of ethyl acetate wasshaken under an initial hydrogen pressure of 52 psi until uptake ceasedafter 1.5hours. The catalyst was removed by filtration and the filtratewas concentrated to a solid which was recrystallized from methanol-waterto give 0.31 g, mp 92°--92°, of N-[3-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₂₆ H₄₅ NO₃ : C, 74.42; H, 10.81; N, 3.34. Found: C,74.53; H, 11.10; N, 3.63.

EXAMPLE 1263-[[3,5-bis[(Decylamino)carbonyl]phenyl](3-ethoxy-3-oxopropyl)amino]propanoicacid ethyl ester

A mixture of 0.50 g (1.09 mmol) of3,5-bis[(decylamino)carbonyl]benzenamine, 0.28 ml (2.18 mmol) of ethyl3-bromopropionate, 0.3 g (2.18 mmol) of potassium carbonate and 0.009 goftetrabutylammonium bromide in 5 ml of DMF was stirred and heated at100° under argon for 24 hours. An additional 1.4 ml (11 mmol) of ethyl3-bromopropionate and 0.33 g (2.18 mmol) of sodium iodide were addedandthe mixture was stirred and heated at 100° for 67 hours. The solvent wasremoved at reduced pressure and the residue was extracted withethylacetate. The extract was washed with NaHCO₃ solution, dried andconcentrated to an oil which was purified by HPLC using 40% ethylacetate-hexane to give 0.27 g (37% yield) of3-[[3,5-bis[(decylamino)carbonyl]phenyl](3-ethoxy-3-oxopropyl)amino]propanoicacid ethyl ester as an oil.

Anal. Calcd for C₃₈ H₆₅ N₃ O₆ : C, 69.16; H, 9.93; N, 6.37. Found: C,69.10; H, 9.96: N, 6.16.

EXAMPLE 1273[[(2-Carboxyethyl)-3,5-bis[(decylamino)carbonyl]phenyl]amino]propanoicacid

A solution of 0.23 g (0.35 mmol) of3-[[3,5-bis[(decylamino)carbonyl]phenyl](3-ethoxy-3-oxopropyl)amino]propanoicacid ethyl ester and 1.4 ml (1.4 mmol) of 1N NaOH in 10 ml of methanolwas stirred at room temperature for 16 hours. The solvent was removed atreduced pressure, the residue was dissolved in water and acidified with0.2 ml of acetic acid. The precipitate was filtered and recrystallizedfrom acetone-hexane to give 0.13 g (60% yield, mp 139°-141°)of3-[[(2-carboxyethyl)-3,5-bis[(decylamino)carbonyl]phenyl]amino]propanoicacid.

Anal. Calcd for C₃₄ H₅₇ N₃ O₆ : C, 67.63; H, 9.51; N, 6.96. Found: C,67.65; H, 9.51; N, 6.92.

The compounds in Table 28 were prepared using the procedure of Example127 if the precursor was a methyl ester or the procedure of Example 125of theprecursor was a benzyl ester.

                                      TABLE 28                                    __________________________________________________________________________     ##STR56##                                                                                                     Microanalytical Data                                                          Calcd    Found                               Ex.                                                                              R         X       mp (°C.)                                                                    E.F.   C  H  N  C  H    N                           __________________________________________________________________________    127a                                                                             CONHC.sub.10 H.sub.21                                                                   (CH.sub.2).sub.2 COOH                                                                 138-140                                                                            C.sub.31 H.sub.53 N.sub.3 O.sub.4                                                    70.02                                                                            10.05                                                                            7.90                                                                             69.97                                                                            10.08                                                                              8.05                        127b                                                                             CONHC.sub.10 H.sub.21                                                                   (CH.sub.2).sub.3 COOH                                                                 111-114                                                                            C.sub.32 H.sub.55 N.sub.3 O.sub.4                                                    70.42                                                                            10.16                                                                            7.70                                                                             70.68                                                                            10.40                                                                              7.73                        127c                                                                             OC.sub.14 H.sub.29                                                                      CH.sub.2 COOH                                                                         38-40                                                                              C.sub.36 H.sub.65 N.sub.3 O.sub.4                                                                *N.O.                            127d                                                                             OCH.sub.2 CHOHC.sub.8 H.sub.17                                                          CH.sub.2 COOH                                                                         111-114                                                                            C.sub.28 H.sub.49 NO.sub.6                                                           67.85                                                                            9.96                                                                             2.83                                                                             67.73                                                                            9.77 2.76                        127e                                                                             COOC.sub.14 H.sub.29                                                                    CH.sub.2 COOH                                                                         86-89                                                                              C.sub.38 H.sub.65 NO.sub.6                                                           72.23                                                                            10.37                                                                            2.22                                                                             72.54                                                                            10.46                                                                              2.26                        __________________________________________________________________________    Not Obtained                                                              

EXAMPLE 1284-[[3,5-bis[(Decylamino)carbonyl]phenyl](4-ethoxy-4-oxobutyl)amino]butanoicacidethyl ester

A mixture of 0.25 g (0.54 mmol) of3,5-bis[(decylamino)carbonyl]benzenamine, 0.48 ml of ethyl4-bromobutyrate, 0.91 g (0.54 mmol) of potassium iodide and 0.15 g (1.09mmol) of potassium carbonate in 10 ml of DMF was stirred at 80° for69hours. An additional 0.48 ml of ethyl 4-bromobutyrate was added and themixture was stirred and heated at 100° for 48 hours. The solvent wasremoved at reduced pressure and the residue was extracted with ethylacetate. The dried extract was concentrated to an oil which was purifiedby chromatography on 13 g of silica gel using 40% ethyl acetate-hexaneto give 0.10 g (21% yield, mp 75°-77°) of4-[[3,5-bis[(decylamino)carbonyl]phenyl](4-ethoxy-4-oxobutyl)amino]butanoicacid ethyl ester. The structure was confirmed by nmr and mass spectra.

EXAMPLE 1294-[[3,5-bis[(Decylamino)carbonyl]phenyl](4-hydroxy-4-oxobutyl)amino]butanoicacid

A solution of 0.099 g (0.14 mmol) of4-[[3,5-bis[(decylamino)carbonyl]phenyl](4-ethoxy-4-oxobutyl)amino]butanoicacid ethyl ester and 0.6 ml (0.6 mmol) of 1N NaOH in 4 ml of methanolwaskept at room temperature for 17 hours. The solvent was removed atreduced pressure and the residue was dissolved in water and acidifiedwith 0.04 mlof acetic acid. The precipitate was filtered andrecrystallized from methanol to give 0.046 g (51% yield, mp 154°-156°)of4-[[3,5-bis[(decylamino)carbonyl]phenyl](4-hydroxy-4-oxobutyl)amino]butanoicacid.

Anal. Calcd for C₃₆ H₆₁ N₃ O₆ : C. 68.43; H, 9.73; N, 6.65. Found: C,68.25: H, 9.53: N, 6.60.

EXAMPLE 130N-[3,5-bis(Decyloxy)phenyl[-N-[2-[2-(diethylamino)ethoxy]-2-oxoethyl]glycine2-(diethylamino)ethyl ester dihydrochloride

A mixture of 0.50 g (0.96 mmol) ofN-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine, 1.3 g (9.6 mmol)of 2-diethylaminoethyl chloride and 1.34 ml (7.7 mmol) ofN,N-diisopropyl ethylamine in 15 ml of DMF was stirred at roomtemperature for 48 hours. The reaction mixture was concentrated on theoil pump and the residue was treated with NaHCO₃ solution. The productwas extracted with ethyl acetate and the dried extract was concentratedat reduced pressure to an oil which was purified by chromatography on 25g of 230-400 mesh silica gel using methylenechloride(90):methanol(10):concentrated ammonium hydroxide(0.1). Theresultant pure free base (0.51 g) was convened to the dihydrochloridesalt by treatment of a methylene chloride solution with 0.95 ml of 3NHCl in ethanol. After concentration, the product was dissolved in etherand stored at -18° until crystals formed. Filtration gave 0.28 g, mp132°-135° of N-[3,5-bis(decyloxy)phenyl]-N-[2-[2-(diethylamino)ethoxy]-2-oxoethyl]glycine 2-(diethylamino)ethylester dihydrochloride.

Anal. Calcd for C₄₂ H₇₇ N₃ O₆.2 HCl: C, 63.61; H, 10.04; N, 5.30; Cl⁻,8.94. Found: C, 63.37; H, 10.01; N, 5.22; Cl⁻, 8.75.

EXAMPLE 131N-[3,5-bis(Decyloxy)phenyl]-N-[[bis(2-hydroxyethyl)amino]carbonyl]methoxy]-2-oxoethyl]glycine[[bis(2-hydroxyethyl)amino]carbonyl]methyl ester

A mixture of 1.0 g (1.92 mmol) ofN-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine, 2.6 ml ofN,N-diisopropylethylamine and a solution ofN,N-bis(2-hydroxyethyl)-2-chloroacetamide [prepared from the reaction of2.1 g (20 mmol) of diethanolamine, 1.6 ml (20 mmol) of chloroacetylchloride and 3.1 ml (22 mmol) of triethylamine in 25 ml of DMF] wasstirred at room temperature for 17 hours. Sodium iodide (3.0 g, 20 mmol)was added and the reaction mixture was stired and heated at 60° underargon for 25 hours. The mixture was concentrated at reduced pressureandNaHCO₃ solution was added to the residue. The product was extracted withethyl acetate and the extract was washed with water, dried andconcentrated to an oil which was crystallized from methylenechloride-ether to give 0.455 g (29% yield, mp 104°-107°) ofN-[3,5-bis(decyloxy)phenyl]-N-[[bis(2-hydroxyethyl)amino]carbonyl]methoxy]-2-oxoethyl]glycine[[bis(2-hydroxyethyl)amino]carbonyl]methyl ester.

Anal. Calcd for C₄₂ H₇₃ N₃ O₁₂ : C, 62.12; H, 9.06; N, 5.17. Found: C,61.79; H, 9.02; N, 5.10.

EXAMPLE 132N-[2-[(Acetyloxy)methoxy]-2-oxoethyl]-N-[3,5-bis(decyloxy)phenyl]glycine(acetyloxy)methyl ester

A mixture of 2.0 g (3.83 mmol) ofN-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine, 1.24 g (11.5 mmol)of chloromethyl acetate, 2.2 ml (15.3 mmol) of triethylamine and 1.15 g(7.7 mmol) of sodium iodide in 100 ml of acetone was stirred at refluxunder argon for 1 hour. DMF (10 ml) was added and reflux was continuedfor49 hours. The solvents were removed at reduced pressure and NaHCO₃solution was added to the residue. The product was extracted with ethylacetate and the dried extract was concentrated to an oil which waspurified by HPLC using 25% ethyl acetate-hexane to give 0.74 g (30%yield,mp 37°-39°) ofN-[2-[(acetyloxy)methoxy]-2-oxoethyl]-N-[3,5-bis(decyloxy)phenyl]glycine(acetyloxy)methyl ester.

Anal. Calcd for C₃₆ H₅₉ NO₁₀ : C, 64.94; H, 8.93; N, 2.10. Found: C,64.49; H, 8.94; N, 2.26.

EXAMPLE 133N-[2-[(Acetyloxy)methoxy]-2-oxoethyl]-N-[3,5-bis[(decylamino)carbonyl)phenyl]glycine(acetyloxy) methyl ester

A mixture of 0.106 g (0.17 mmol) ofN-(carboxymethyl)-N-[3,5-bis[(decylamino) carbonyl]phenyl]glycine, 0.107g(0.87 mmol) of chloromethyl acetate, 0.07 ml (0.5 mmol) oftriethylamine and 0.051 g (0.33 mmol) of sodium iodide in 3 ml ofanhydrous acetone was stirred at reflux under argon for 26 hours. Thesolvent was removed, NaHCO₃ solution was added to the residue and theproduct was extracted with ethyl acetate. The dried extract wasconcentrated to an oilwhich was purified by chromatography on 20 g ofsilica gel using 50% ethyl acetate-hexane to give 0.058 g ofN-[2-[(acetyloxy)methoxy]-2-oxoethyl]-N-[3,5-bis[(decylamino)carbonyl]phenyl]glycine (acetyloxy) methyl ester as a waxy solid.

Anal. Calcd for C₃₈ H₆₁ N₃ O₁₀ : C, 63.40; H, 8.54; N, 5.84. Found: C,63.47; H, 8.47; N, 5.70.

EXAMPLE 134N-[3,5-bis[(Decylamino)carbonyl]phenyl]-N-[2-[(2,2-dimethyl-1-oxopropoxy)methoxy]-2-oxoethyl]glycine(2,2-dimethyl-1-oxopropoxy)methyl ester

A mixture of 0.1023 g (0.174 mmol) ofN-(carboxymethyl)-N-[3,5-bis[(decylamino)carbonyl]phenyl]glycine, 0.12ml (0.84 mmol) of chloromethyl pivalate, 0.07 ml (0.49 mmol) oftriethylamineand 0.04 1 g of sodium iodide in 3 ml of anhydrous acetonewas stirred at reflux under argon for 17 hours. The solvent was removed,NaHCO₃ solution was added to the residue and the product was extractedwith ethylacetate. The dried extract was concentrated to an oil andpurified by chromatography on 20 g of silica gel using 50% ethylacetate-hexane to give 0.093 g (66% yield) ofN-[3,5-bis[(decylamino)carbonyl]phenyl]-N-[2-[(2,2-dimethyl-1-oxopropoxy)methoxy]-2-oxoethyl]glycine(2,2-dimethyl-1-oxopropoxy)methyl ester as a waxy solid.

Anal. Calcd for C₄₄ H₇₃ N₃ O₁₀ : C, 65.72; H, 9.15; N, 5.23. Found: C,65.23; H, 9.27; N, 5.18.

EXAMPLE 135 N-(3-Hydroxyphenyl)-N-(2-methoxy-2-oxoethyl)glycine methylester

A mixture of 1.85 g (0.0093 mol) of 3-dimethylethyloxyaniline, 4.4 ml(0.0465 mol) of methyl bromoacetate, 8.0 g (0.037 mol) of1,8-bis(dimethylamino)naphthalene and 1.4 g (0.0093 mol) of sodiumiodide in 100 ml of dry acetonitrile was stirred at reflux for 41 hours.The reaction mixture was filtered, the filtrate was concentrated and theresidue was extracted with ethyl acetate. The extract was washed with 1NHCl, with NaHCO₃ solution, dried and concentrated to an oil whichwaspurified by chromatography on 150 g of silica gel using 30% ethylacetate-hexane to give 2.73 g (88% yield) ofN-(2-methoxy-2-oxoethyl)-N-[3-(phenylmethoxy)phenyl]glycine methylester. This was dissolved in 60 ml of ethyl acetate, 0.5 g of 10%palladium on carbon was added and the mixture was shaken under aninitial hydrogen pressure of 53 psi on a Parr Hydrogenator for 20 hours.An additional 0.5 g of 10% palladium on carbon was added and shakingunder hydrogen pressurewas continued for 20 hours. The catalyst wasmoved by filtration and the filtrate was concentrated to an oil whichwas purified by chromatography on 175 g of silica gel using 50% ethylacetate-hexane to give 1.32 g ofN-(3-hydroxyphenyl)-N-(2-methoxy-2-oxoethyl)glycine methyl ester as anoil. The structure was confirmed by nmr and mass spectra.

EXAMPLE 136 4-[(Decylamino)carbonyl]nitrobenzene

To a solution of 5.4 ml (0.027 mol) of decylamine and 5.6 ml (0.04 mol)of triethylamine in 20 ml of methylene chloride cooled in an ice bathwas added dropwise a solution of 5.0 g (0.027 mol) of 4-nitrobenzoylchloride in 40 ml of methylene chloride. The reaction mixture wasstirred in the ice bath for 30 minutes, at room temperature for 15minutes and kept at 0° for 18 hours. After dilution with methylenechloride, the mixture was washed with 0.5N NaOH and the extract wasdried and concentrated to a solid. Recrystallization from methylenechloride-hexane gave 8.1 g (98% yield, mp 89°-91°) of4-[(decylamino)carbonyl]nitrobenzene. The nmr was consistent with thestructure.

Using this procedure, 2-nitrobenzoyl chloride gave2-[(decylamino)carbonyl]nitrobenzene, mp 55°-57° in 95% yield.

EXAMPLE 137 4-[(Decylamino)carbonyl]benzenamine

A mixture of 8.05 g of 4-[(decylamino)carbonyl]nitrobenzene and 2.5 g of10% palladium on carbon in 175 ml of THF was shaken under an initialhydrogen pressure of 54 psi in a Parr Hydrogenator for 17 hours. Thecatalyst was removed by filtration and the filtrate was concentrated toa solid which was triturated with hexane and filtered to give 6.88 g(95% yield, mp 117°-119°) of 4-[(decylamino)carbonyl]benzenamine.Thestructure was confirmed by the nmr spectrum.

Using this procedure 2-[(decylamino)carbonyl]nitrobenzene gave2-[(decylamino)carbonyl]benzenamine, mp 72°-74°, in 91% yield.

EXAMPLE 138N-[4-[(Decylamino)carbonyl]phenyl]-N-[2-methoxy-2-oxoethyl)glycinemethyl ester

A mixture of 4.0 g (0.0145 mol) of 4-[(decylamino)carbonyl]benzenamine,20.5 ml (0.217 mol) of methyl bromoacetate, 4.0 g (0.029 mol) ofpotassiumcarbonate, 4.3 g (0.029 mol) of sodium iodide and 0.21 g 0.65mmol) of tetrabutylammonium bromide in 40 ml of anhydrous DMF wasstirred and heated at 100° for 69 hours. The solvent was removed on theoil pump and the residue was extracted with ethyl acetate. The extractwas washed with NaHCO₃ solution, dried and concentrated to an oil whichwas purified by chromatography on 40 g of silica gel using 75% ethylacetate-hexane. The pure fractions were combined, concentrated andrecrystallized three times from methylene chloride-ether to give 1.98 g(33% yield, mp 104°-106°) ofN-[4-[(decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester.

Anal. Calcd for C₂₃ H₃₆ N₂ O₅ : C, 65.69; H, 8.63; N, 6.66. Found: C,65.34; H, 8.76; N, 6.58.

Using this procedure 2-[(decylamino)carbonyl]benzenamine gaveN-[2-[(decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, mp 35°-38°, in 35% yield.

Anal. Calcd for C₂₃ H₃₆ N₂ O₅ : C, 65.69; H, 8.63; N, 6.66. Found: C,65.12; H, 8.67: N, 6.49.

EXAMPLE 139 N-(Carboxymethyl)-N-[4-[(decylamino)carbonyl]phenyl]glycine

A solution of 1.88 g (4.47 mmol) ofN-[4-[(decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester and 17.9 ml (17.9 mmol) of 1N NaOH in 125 ml of methanolwas kept atroom temperature for 18 hours. The solvent was removed, waterwas added to the residue and the pH was adjusted to 2 with 6N HCl. Theprecipitate was filtered and recrystallized from methanol-water to give1.63 g (93% yield,mp 155°-157°) ofN-(carboxymethyl)-N-[4-[(decylamino)carbonyl]phenyl]glycine.

Anal. Calcd for C₂₁ H₃₂ N₂ O₅ : C, 64.26; H, 8.22; N, 7.14. Found: C,64.36; H, 8.26; N, 7.17.

Using this procedureN-[2-[(decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester gaveN-(carboxymethyl)-N-[4-[(decylamino)carbonyl]phenyl]glycine as an oil.

Anal. Calcd for C₂₁ H₃₂ N₂ O₅ : C, 64.26; H, 8.22; N, 7.14. Found: C,64.46; H, 8.29; N, 7.04.

EXAMPLE 140 N-[2,5-bis[(Decylamino)carbonyl]nitrobenzene

A mixture of 10 g (0.047 mol) of nitroterephthalic acid, 40 ml ofthionyl chloride and 1 ml of anhydrous DMF was stirred at reflux for 5hours. The reaction mixture was concentrated at reduced pressure and theresidual acid chloride was dissolved in anhydrous THF and added dropwiseover 30 minutes to a stirred, ice bath cooled solution of 25 ml (0.126mol) of decylamine and 15 ml (0.108 mol) of triethylamine in 100 ml ofanhydrous THF. Additional THF (50 ml) was added and stirring wascontinued for 17 hours at room temperature. Water (1 L) was added andthe precipitate was filtered and recrystallized from methanol-water togive 20.4 g, mp 159°-160° ofN-[2,5-bis[(decylamino)carbonyl]nitrobenzene.

Anal. Calcd for C₂₈ H₄₇ N₃ O₄ : C, 68.68; H, 9.67; N, 8.58. Found: C,68.81; H, 9.72; N, 8.62.

EXAMPLE 141 N-[2,5-bis]Decylamino)carbonyl]benzenamine

A mixture of 15 g of N-[2,5-bis[(decylamino)carbonyl]nitrobenzene and 1g of 10% palladium on carbon in 200 ml of THF was shaken under aninitial hydrogen pressure of 52 psi on a Parr Hydrogenator for 18 hours.The catalyst was removed by filtration and the filtrate was concentratedto a solid which was crystallized three times from methylenechloride-methanol to give 3.85 g, mp 170°-172°, ofN-[2,5-bis[decylamino)carbonyl]benzenamine.

Anal. Calcd for C₂₈ H₄₉ N₃ O₂ : C, 73.16; H, 10.74; N, 9.14. Found: C,73.13; H, 10.53: N, 9.09.

EXAMPLE 142N-[2,5-bis[(Decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester

A mixture of 1.0 g (2.18 mmol) ofN-[2,5-bis[decylamino)carbonyl]benzenamine, 3.0 ml (32.7 mmol) of methylbromoacetate, 0.55 g (4 mmol) of potassium carbonate, 0.6 g (4 mmol) ofsodium iodide and 0.065 g of tetrabutylammonium bromide in 15 ml ofanhydrous DMF was stirred and heated at 100° for 48 hours. The solventwas removed on the oil pump and the residue was taken up in ethylacetate. The extract was washed with NaHCO₃ solution, dried andconcentrated to an oil which was purified by chromatography on 100 g ofsilica gel using 40% ethyl acetate-hexane to give an oil which wascrystallized from methanol-water to give 0.308 g, mp 76°-78°, ofN-[2,5-bis[(decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester.

Anal. Calcd for C₃₄ H₅₇ N₃ O₆ : C, 67.63; H, 9.51; N, 6.96. Found: C,67.49; H, 9.46; N, 7.02.

EXAMPLE 143N-(Carboxymethyl)-N-[2,5-bis[(decylamino)carbonyl]phenyl]glycine

A solution of 0.3 g (0.5 mmol)ofN-[2,5-bis[(decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester and 3.0 ml (3mmol) of 1N NaOH in 25 ml of methanol was leftat room temperature for 40 hours. The solvent was removed, water wasaddedto the residue and the pH was adjusted to 3-4 with acetic acid. Theproductwas extracted with ethyl acetate and the dried extract wasconcentrated to an oil which was crystallized from methanol-water togive 0.25 g, mp 135°-136°, ofN-(carboxymethyl)-N-[2,5-bis[(decylamino)carbonyl]phenyl]glycine.

Anal. Calcd for C₃₂ H₅₃ N₃ O₆ : C, 66.75; H, 9.28; N, 7.30. Found: C,66.78; H, 9.14; N, 7.32.

EXAMPLE 144 N-(2-Methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[5-[2,3-bisphenylmethoxy)phenyl]pentoxy]phenyl]glycinemethyl ester

A mixture of 0.903 g (1.73 mmol) ofN-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 0.80 g (1.82 mmol) of1-(5-bromopentyl)-2,3-bis(phenylmethoxy)benzene, 0.48 g (3.46 mmol) ofpotassium carbonate and 0.26 g (1.73 mmol) of sodium iodide in 30 ml ofacetone and 6 ml of DMF was stirred at reflux under argon for a total of120 hours. After 48 and 96 hours, additional 0.4 g portions of1-(5-bromopentyl)-2,3-bis(phenylmethoxy)benzene were added. Additionalpotassium carbonate (0.2 g) was also added after 96 hours. The reactionmixture was filtered through a Celite pad and the filtrate wasconcentrated at reduced pressure to a yellow oil. Purification by HPLCusing 20% ethyl acetate-hexane gave 1.086 g (71% yield) ofN-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[5-[2,3-bisphenylmethoxy)phenyl]pentoxy]phenyl]glycinemethyl ester.

Anal. Calcd for C₅₅ H₇₇ NO₈ : C, 75.05; H, 8.82, N, 1.59. Found: C,75.17; H, 8.87; N, 1.43.

EXAMPLE 145N-(Carboxymethyl)-N-[3-(octadecyloxy)-5-[5-[2,3-bis(phenylmethoxy)phenyl]pentoxy]phenyl]glycine

A solution of 1.06 g (1.2 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[5-[2,3-bisphenylmethoxy)phenyl]pentoxy]phenyl]glycinemethyl ester and 0.8 ml (4.8 mmol) of 6N NaOH in 35 ml of methanol and10 ml of dioxane was stirred at reflux under argon for 4.5 hours. Thesolvent was removed at reduced pressure and the residue was acidifiedand extracted with ethyl acetate. The dried extract was concentrated toa solid which was recrystallized from methanol to give0.93 g (91% yield,mp 79°-81°) ofN-(carboxymethyl)-N-[3-(octadecyloxy)-5-[5-[2,3-bis(phenylmethoxy)phenyl]pentoxy]phenyl]glycine.

Anal. Calcd for C₅₃ H₇₃ NO₈ : C, 74.70; H, 8.63; N, 1.64. Found: C,74.71; H, 8.44; N, 1.48.

EXAMPLE 146 N-Carboxymethyl)-N-[3-[5-(2,3-dihydroxyphenyl)pentoxy]-5-(octadecyloxy)phenyl]glycine

A mixture of 0.918 g ofN-(carboxymethyl)-N-[3-(octadecyloxy)-5-[5-[2,3-bis(phenylmethoxy)phenyl]pentoxy]phenyl]glycineand 0.3 g of 10% palladium on carbon in 50 ml of tetrahydrofuran wasstirred under a hydrogen atmosphere for 4 hours when absorption ceased.The catalyst was removed by filtration through a Celitepad and thefiltrate was concentrated to a solid which was triturated with hexaneand filtered to give 0.653 g (92% yield, mp 129°-131°) ofN-(carboxymethyl)-N-[3-[5-(2,3-dihydroxyphenyl)pentoxy]-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₃₉ H₆₁ NO₈ : C, 69.72; H, 9.15; N, 2.08. Found: 69.72;H, 9.23; N, 2.10.

EXAMPLE 147N-(2-Methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[(2-quinolinyl)methoxy]phenyl]glycinemethyl ester

A mixture of 1.5 g (2.9 mmol) ofN-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 0.935 g (4.35 mmol) of 2-(chloromethyl)quinolinehydrochloride (Lancaster Organic Research Chemicals), 2.0 g (14.5 mmol)ofpotassium carbonate and 0.435 g (2.9 mmol) of sodium iodide in 100 mlof acetone and 20 ml of DMF was stirred at reflux under argon for 24hours. The solvents were removed at reduced pressure and the residue wastreated with water and the product was extracted with ethyl acetate. Thedried extract was concentrated to a solid which was purified by HPLCusing 30% ethyl acetate-hexane followed by recrystallization from hexaneto give 1.5g (78% yield, mp 76°-79°) ofN-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[(2-quinolinyl)methoxy]phenyl]glycinemethyl ester.

Anal. Calcd for C₄₀ H₅₈ N₂ O₆ : C, 72.47; H, 8.82; N, 4.23. Found: C,72.48; H, 8.93; N, 4.03.

EXAMPLE 148N-(Carboxymethyl)-N-[3-(octadecyloxy)-5-[(2-quinolinyl)methoxy]phenyl]glycine

A solution of 1.5 g (2.26 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[(2-quinolinyl)methoxy]phenyl]glycinemethyl ester and 2.0 ml (12 mmol) of 6N NaOH in 80 ml of methanol wasstirred at reflux for 4 hours. The solvent was removed at reducedpressure, the residue was acidified and the product was removedbyfiltration. Recrystallization from THF-acetone gave 1.0 g (70% yield,mp 172°-174°) ofN-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(2-quinolinyl)methoxy]phenyl]glycine.

Anal. Calcd for C₃₈ H₅₄ N₂ O₆ : C, 71.89; H, 8.57; N, 4.41. Found: C,71.87; H, 8.78; N, 4.23.

EXAMPLE 149N-[3-[3-Bromopropoxy)-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester

A mixture of 4.0 g (7.67 mmol) ofN-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 7.8 ml (76.7 mmol) of 1,3-dibromopropane and 5.3 g (38.3mmol) of potassium carbonate in 75 ml of acetone and 15 ml of DMF wasstirred at reflux under argon for 41 hours. The reaction mixture wasfiltered through a Celite pad and the filtrate was concentrated to asolidwhich was purified by HPLC using 5% ethyl acetate-toluene to give3.5 g (72% yield, mp 67°-69°) ofN-[3-(3-bromopropoxy)-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester. The structure was confirmed by the nmr spectrum.

Anal. Calcd for C₃₃ H₅₆ BrNO₆ : C, 61.67; H, 8.78; N, 2.18; Br, 12.43.Found: C, 62.68; H, 9.08; N, 2.12; Br, 11.86.

EXAMPLE 1501-[3-[3-[bis(Carboxymethyl)amino]-5-(octadecyloxy)phenoxy]propyl]pyridiniumhydroxide

A solution of 0.76 g ofN-[3-(3-bromopropoxy)-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester in 40 ml of pyridine was stirred and heated at 100°for 38hours. The excess pyridine was removed on the oil pump to a brown solidwhich was recrystallized from methylene chloride-ether to give 0.58 g(68% yield, mp 120°-123°) of the pyridinium bromide intermediate whichwas hydrolyzed by dissolving in 20 ml of methanol containing 0.52 ml of6N NaOH and stirring at room temperature for 22 hours. The solvent wasremoved at reduced pressure and the residue was acidified and theproduct was removed by centrifugation. Recrystallizationfrommethanol-water gave 0.197 g, mp 124°-127°, of1-[3-[3-[bis(carboxymethyl)amino]-5-(octadecyloxy)phenoxy]propyl]pyridiniumhydroxide.

Anal. Calcd for C₃₆ H₅₇ N₂ O₆.1:1 OH: C, 68.54; H, 9.27; N, 4.44. Found:C, 68.52; H, 9.14; N, 4.29.

EXAMPLE 151N-[(Carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-(octadecyloxy)phenyl]glycine

A solution of 1.76 g (2.58 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-octadecyloxy-5-(3,6,9-trioxaundec-1-yloxy)phenyl]glycinemethyl ester and 2.2 ml (12.9 mmol) of 6N NaOH in 75 ml of methanol waskept at room temperature for 70 hours. The solvent was removed atreduced pressure and the residue was acidified to pH 2. The product wasextracted with ethyl acetate and the dried extract was concentrated atreduced pressure to a solid which was triturated with hexane andfiltered to give 1.62 g (96% yield, mp 76°-78°) ofN-[(Carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₃₆ H₆₃ NO₉ : C, 66.13; H, 9.71; N, 2.14. Found: C,66.01; H, 9.90; N, 2.08.

EXAMPLE 152N-(2-Methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6-naphthalenyl]butoxy]phenyl]glycinemethyl ester

A mixture of 1.5 g (2.88 mmol) ofN-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 1.24 g (2.88 mmol) of2-(4-chlorobutyl)-6,7-bis(phenylmethoxy) naphthalene, 0.8 g (5.75 mmol)ofpotassium carbonate and 0.43 g (2.88 mmol) of sodium iodide in 50 mlof acetone and 10 ml of DMF was stirred at reflux under argon for 40hours. The acetone was removed by distillation and 50 ml of DMF, 1.24 gof 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy)naphthalene, 0.8 g ofpotassium carbonate and 0.43 g of sodium iodide were added and themixture was stirred and heated at 85° for 4 days. The DMF was removedusing an oil pump at 55°. The residue was extracted with methylenechloride,the extract was concentrated and the product was purified byHPLC using 20%ethyl acetate-hexane to give 1.3 g (49% yield) of N-(2-methoxy-2oxoethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6-naphthalenyl]butoxy]phenyl]glycinemethyl ester as a semisolid. The nmr and mass spectra were consistentwith the structure.

EXAMPLE 153N-(Carboxymethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6naphthalenyl]-butoxy]phenyl]glycine

A solution of 1.3 g (1.42 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6-naphthalenyl]butoxy]phenyl]glycinemethyl ester and 0.95 ml (5.68 mmol) of 6N NaOH in 40 ml of methanol and15 ml of dioxane was stirred at refluxunder argon for 5 hours. Thesolvents were removed at reduced pressure, theresidue was acidified andthe product was extracted with ethyl acetate. Thedried extract wasconcentrated to a solid which was recrystallized from methylenechloride-methanol to give 1.18 g, mp 83°-86°, ofN-(carboxymethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6-naphthalenyl]butoxy]phenyl]glycine.The nmr and mass spectra were consistent with the structure.

Anal. Calcd for C₅₆ H₇₃ NO₈ : C, 75.73; H, 8.28; N, 1.58. Found: C,74.59; H, 8.42; N, 1.54.

EXAMPLE 154N-(Carboxymethyl)-N-[3-[4-(2,3-dihydroxy-6-naphthalenyl)butoxy]-5-(octadecyloxy)phenyl]glycine

A mixture of 1.16 g ofN-(carboxymethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6-naphthalenyl]butoxy]phenyl]glycineand 0.35 g of 10% palladium on carbon in 75 ml of THF was stirred undera hydrogen atmosphere until uptake ceased after 6 hours. The catalystwas removed by filtration through a Celite padand the filtrate wasconcentrated to a solid which was triturated with hexane and filtered togive 0.835 g (90% yield, mp 153°-155°) ofN-(carboxymethyl)-N-[3-[4-(2,3-dihydroxy-6-naphthalenyl)butoxy]-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₄₂ H₆₁ NO₈ : C, 71.26; H, 8.69; N, 1.98. Found: C,71.74; H, 8.79: N, 1.93.

EXAMPLE 155N-(Carboxymethyl)-N-[3,5-bis[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]phenyl]glycine

A mixture of 2.0 g (7.43 mmol) ofN-[(3,5-dihydroxy)phenyl]-N-(2-methoxy-2-oxoethyl) glycine methyl ester,4.3 g (17.8 mmol) of 2-[2-(2-ethoxyethoxy)ethoxy]ethyl bromide, 2.2 g(14.9 mmol) of sodium iodide and 3.1 g (22.3 mmol) of potassiumcarbonate in 50 ml of acetone and 25 ml of DMF was stirred at refluxunder argon for96 hours. The solvents were removed at reduced pressureand the residual oil was purified by HPLC using 75% ethyl acetate-hexaneto give 1.46 g (33% yield) ofN-[3,5-bis[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester as a yellow oil.

Anal. Calcd for C₂₈ H₄₇ NO₁₂ : C, 57.03; H, 8.03; N, 2.38. Found: C,57.08; H, 8.15; N, 2.32.

A solution of 1.41 g (2.39 mmol) of this dimethyl ester and 1.6 ml (9.56mmol) of 6N NaOH in 50 ml of methanol was stirred at reflux under argonfor 4 hours. The methanol was removed at reduced pressure, the residuewasacidified and the product was extracted with ethyl acetate. The driedextract was concentrated to give 1.32 g ofN-(carboxymethyl)-N-[3,5-bis[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]phenyl]glycineas an oil.

Anal. Calcd for C₂₆ H₄₃ NO₁₂ : C, 55.60; H, 7.72; N, 2.49. Found: C,55.89; H, 7.78; N, 2.48.

EXAMPLE 156N-(Carboxymethyl)-N-[3-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-5-(octadecyloxy)phenylglycine

A mixture of 2.0 g (3.83 mmol) ofN-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 4.15 g (15.3 mmol) of2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethyl bromide, 1.2 g (7.66 mmol)ofsodium iodide and 1.6 g (11.5 mmol) of potassium carbonate in 60 ml ofacetone and 30 ml of DMF was stirred at reflux for 48 hours. Thesolvents were removed at reduced pressure and the residual oil waspurified by HPLCusing 60% ethyl acetate-hexane to give 2.01 g (73%yield) ofN-[3-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester. The nmr and mass spectra were consistent with thestructure.

A solution of 2.0 g (2.81 mmol) ofN-[3-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester and 2.4 ml (14 mmol) of 6N NaOH in 75 ml of methanol wasstirred at room temperature for 22 hours. The solvent was removed atreduced pressure, the residue was acidified andthe product was extractedwith ethyl acetate. The dried extract was concentrated to a solid whichwas triturated with hexane and filtered to give 1.58 g (82% yield, mp63°-65°) ofN-(carboxymethyl)-N-[3-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-5-(octadecyloxy)phenylglycine.

Anal. Calcd for C₃₇ H₆₅ NO₁₀ : C, 64.98; H; 9.58, N, 2.05. Found: C,64.75; H, 9.51; N, 1.89.

EXAMPLE 157N-(Carboxymethyl)-N-[3-[2-[2-[2-(ethoxyethoxy)ethoxy]ethoxy]-5-(tetradecyloxy)-phenyl]glycine

A mixture of 0.925 g (1.99 mmol) ofN-[3-hydroxy-5-(tetradecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 1.9 g (7.95 mmol) of 2-[2-(2-ethoxyethoxy)ethoxy]ethylbromide, 0.6 g (3.97 mmol) of sodium iodide and 0.83 g (5.96 mmol) ofpotassium carbonate in 30 ml of acetone and 15 ml of DMF was stirred atreflux under argon for 48 hours. The solvents were removed at reducedpressure and the residue was purified by HPLC using 40% ethylacetate-hexane to give 0.95 g (77% yield) ofN-[3-[2-[2-[2-(ethoxyethoxy)ethoxy]ethoxy]-5-(tetradecyloxy)phenyl]glycine-N-(2-methoxy-2-oxoethyl)glycinemethyl ester as an oil. The nmr and mass spectra were consistent withthe structure.

A solution of this dimethyl ester (0.95 g, 1.52 mmol) and 1.3 ml of 6NNaOHin 40 ml of methanol was stirred at room temperature for two days.The methanol was removed at reduced pressure, the residue was acidifiedand the product was extracted with ethyl acetate. The dried extract wasconcentrated to a solid which was triturated with hexane and filtered togive 0.83 g (92% yield, mp 65°-67°) ofN-(carboxymethyl)-N-[3-[2-[2-[2-(ethoxyethoxy)ethoxy]ethoxy]-5-(tetradecyloxy)phenyl]glycine.

Anal. Calcd for C₃₂ H₅₅ NO₉ : C, 64.30; H, 9.27; N, 2.34. Found: C,64.29; H, 9.34; N, 2.38.

EXAMPLE 158N-(2-Methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycinemethyl ester

A mixture of 1.0 g (1.92 mmol) ofN-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 0.8 g (2.88 mmol) of 1-(3-bromopropoxy)-4-(methylsulfinyl)benzene, 0.3 g (1.92 mmol) of sodium iodide and 0.53 g (3.83 mmol) ofpotassium carbonate in 30 ml of acetone and 6 ml of DMF was stirred atreflux under argon for 72 hours. The solvents were removed at reducedpressure and the residual oil was purified by HPLC using 50% ethylacetate-toluene to give 0.76 g (55% yield, mp 67°-69°) ofN-(2-methoxy-2-oxoethyl)-N-[3-[3-[4-methylsulfinyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycinemethyl ester.

Anal. Calcd for C₄₀ H₆₃ NO₈ S: C, 66.91; H, 8.84; N, 1.95; S, 4.47.Found: C, 66.60; H, 8.92; N, 2.06; S, 4.65.

EXAMPLE 159N-(Carboxymethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-(octadecyloxy)phenylglycine

A solution of 0.73 g (1.02 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycinemethyl ester and 0.68 ml (4.08 mmol) of 6N NaOH in 30 ml of methanol wasstirred at reflux under argon for 4 hours. The methanol was removed atreduced pressure, the residue was acidified and the product wasextracted with ethyl acetate. The dried extract was concentrated to asolid which was recrystallized from acetone-hexane to give 0.57 g (82%yield, mp 124°-126°) ofN-(carboxymethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-(octadecyloxy)phenylglycine.

Anal. Calcd for C₃₈ H₅₉ NO₈ S: C, 66.15; H, 8.62; N, 2.03; S, 4.65.Found: C, 66.21; H, 8.71; N, 2.00; S, 4.35.

EXAMPLE 160N-(2-Methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfonyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycinemethyl ester

A mixture of 1.0 g (1.92 mmol) ofN-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 0.84 g (2.88 mmol) of1-(3-bromopropoxy)-4-(methylsulfonyl) benzene, 0.53 g (3.83 mmol) ofpotassium carbonate and 0.3 g (1.92 mmol) of sodium iodide in 30 ml ofacetone and 6 ml of DMF was stirred at refluxunder argon for 72 hours.The solvents were removed at reduced pressure andthe residual oil waspurified by three recrystallizations from methylene chloride-methanol togive 1.03 g (73% yield, mp 70°-72°) ofN-(2-methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfonyl)phenoxy]propoxy]-5-(octadecyloxy)-phenyl]glycinemethyl ester.

Anal. Calcd for C₄₀ H₆₃ NO₉ S: C, 65.45; H, 8.65; N, 1.91 S,4.37. Found:C, 65.18; H, 8.73; N, 1.88; S, 4.46.

EXAMPLE 161N-(Carboxymethyl)-N-[3-[3-[4-(methylsulfonyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine

A solution of 1.01 g (1.37 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfonyl)phenoxy]propoxy]-5-(octadecyloxy)-phenyl]glycine methyl ester and 0.92ml (5.5 mmol) of 6N NaOH in 30 ml of methanol was stirred at reflux for4 hours under argon. The methanol was removed at reduced pressure, theresidue was acidified and the product was extracted with ethyl acetate.The dried extract was concentrated to a solid which was recrystallizedfrom methylene chloride-ether to give 0.835 g (86% yield, mp 118°-120°)ofN-(carboxymethyl)-N-[3-[3-[4-(methylsulfonyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₃₈ H₅₉ NO₉ S: C, 64.65; H, 8.42; N, 1.98; S, 4.54.Found: C, 64.75; H, 8.49; N, 1.93; S, 4.29.

EXAMPLE 162N-(Carboxymethyl)-N-[3-(octadecyloxy)-5-[[(trifluoromethyl)sulfonyl]amino]phenyl]glycine

To 0.25 g (0.48 mmol) ofN-[3-amino-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl) glycinemethylester and 0.1 ml (0.72 mmol) of triethylamine in 4 ml of anhydrousmethylene chloride cooled in an ice bath was added 0.08 ml (0.48 mmol)of trifluoromethanesulfonic anhydride in 1 ml of methylene chloride.After one hour, an additional 0.01 mi of trifluoromethanesulfonicanhydride was added. The mixture was stirred for 30 minutes, and it waswashed with NaHCO₃ solution, dried and concentrated at reduced pressureto a solid. Purification by chromatography on 15 g of silica gel using50% ethyl acetate-hexane gave 0.176 g, mp 96°-98° (56% yield)ofN-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[[(trifluoromethyl)sulfonyl]aminophenyl]glycinemethyl ester. The structure was confirmed by nmr and mass spectra. Asolution of 0.17 g (0.26 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[[(trifluoromethyl)sulfonyl]aminophenyl]glycinemethyl ester in 10 ml methanol and 0.22 ml (1.3 mmol) of 6N NaOH wasstirred at reflux under an argon atmosphere for 2 hours. The solvent wasremoved at reduced pressure and the residue was dissolved in water andacidified with 6N HCl. The resultant precipitate was extracted withethyl acetate and the dried extract was concentrated to a solid whichwas triturated with hexane and filtered to give 0.15 g (95% yield), mp163°-165°, ofN-(carboxy-methyl)-N-[3-(octadecyloxy)-5-[[(trifluoromethyl)sulfonyl]amino]phenyl]glycine.

Anal. Calcd for C₂₉ H₄₇ F₃ N₂ O₇ S: C, 55.75; H, 7.58; N, 4.48; F, 9.12;S, 5.13. Found: C, 55.34; H, 7.60; N, 4.40; F, 8.97; S, 4.84.

EXAMPLE 163 3-(Methylthio)-5-(octadecyloxy)benzoic acid

A mixture of 2.54 g (12.8 mmol) of 3-hydroxy-5-methylthiobenzoic acidmethyl ester, 4.7 g (14.1 mmol) of 1-bromooctadecane and 2.7 g (19.2mmol)of potassium carbonate in 60 ml of anhydrous DMF was stirred andheated at 80° under an argon atmosphere for 21 hours. The reactionmixture was filtered through a Celite pad and the filtrate wasconcentrated at reduced pressure. Water was added to the residue and theproduct was filtered and recrystallized from methylene chloride-methanolto give 5.5 g(95% yield), mp 64°-66°, of3-(methylthio)-5-(octadecyloxy)benzoic acid methyl ester. The nmr andmassspectra were consistent with the structure. A solution of 2.7 g (6mmol) of3-(methylthio)-5-(octadecyloxy)benzoic acid methyl ester and 5.0ml (30 mmol) of 6N NaOH in 125 ml of methanol was stirred at refluxunder argon for 5 hours. The solvent was removed at reduced pressure,the residue was acidified with 6N HCl and the product was extracted withchloroform. The dried extract was concentrated to a solid which wastriturated with hexaneand filtered to give 2.6 g, mp 90°-92°, of3-(methylthio)-5-(octadecyloxy)benzoic acid. The nmr and mass spectrawereconsistent with the structure.

EXAMPLE 164 3-(Methylthio)-5-(octadecyloxy)benzenamine

A mixture of 2.57 g (5.89 mmol) of3-(methylthio)-5-(octadecyloxy)benzoic acid, 1.5 ml (7.1 mmol) ofdiphenylphosphoryl azide 5.5 ml (58.9 mmole) t-butanol and 1.0 ml (7.1mmol) of triethylamine in 25 ml of anhydrous toluene was stirred atreflux under argon for 19 hours. The reaction mixture was concentratedat reduced pressure and the product was extractedwith methylenechloride. The extract was washed with NaHCO₃ solution and the driedextract was concentrated to a solid which was purified by chromatographyon 20 g of silica gel using 50% methylene chloride-hexane to give 2.67 g(89% yield), mp 73°-75°, of3-(methylthio)-5-(octadecyloxy)phenylcarbamic acid dimethylethyl ester.The nmr and mass spectra were consistent with the structure.

A solution of 2.65 g (5.2 mmol) of3-(methylthio)-5-(octadecyloxy)phenylcarbamic acid dimethylethyl esterand2.0 ml (26 mmol) of trifluoroacetic acid in 50 ml of methylenechloride waskept at room temperature for 24 hours. The mixture wasconcentrated at reduced pressure and the residue was treated with excessNaHCO₃ solution. The product was extracted with methylene chloride andthe dried extract was concentrated and recrystallized from methylenechloride-hexaneto give 1.85 g (87% yield), nap 75°-77° of3-(methylthio)-5-(octadecyloxy)benzenamine. The nmr and mass spectrawere consistent with the structure.

EXAMPLE 165N-(2-Methoxy-2-oxoethyl)-N-[3-(methylthio)-5-(octadecyloxy)phenyl]glycinemethyl ester and[[3-bis(2-methoxy-2-oxoethyl)amino]-5-(octadecyloxy)phenyl]thio]aceticacid methyl ester

A mixture of 1.83 g (4.49 mmol) of3-(methylthio)-5-(octadecyloxy)benzenamine, 1.3 ml (13.5 mmol) of methylbromoacetate, 2.4 g (11.2 mmol) of 1,8-bis(dimethylamino)naphthalene and0.2 g (1.3 mmol) of sodium iodide in 40 ml of acetonitrile and 10 ml ofDMF was stirred and heated at reflux under argon for 48 hours. Thereaction mixture was filtered, the filtrate was concentrated to a solidwhich was treated with 200 ml of 0.5N HCl and the product was extractedwith ethyl acetate. The extract was washed with NaHCO₃ solution, driedand concentrated to a solid which was purified by HPLC using 20% ethylacetate-hexane to give 0.32 g (13% yield), mp78°-80°, ofN-(2-Methoxy-2-oxoethyl)-N-[3-(methylthio)-5-(octadecyloxy)phenyl]glycinemethyl ester. The structure was confirmed by nmr and mass spectra whichwere compatible. Later fractions from the HPLC were concentrated to give0.83 g which was further purified by chromatography on 40 g of silicagel using 20% ethyl acetate-hexane to give 0.50 g (18% yield), mp68°-70°, of[[3-bis(2-methoxy-2-oxoethyl)amino]-5-(octadecyloxy)phenyl]thio]aceticacid methyl ester. The structure was confirmed by nmr and mass spectrawhich were compatible.

EXAMPLE 166N-(Carboxymethyl)-N-[3-(methylthio)-5-(octadecyloxy)phenyl]glycine

A solution of 0.32 g (0.58 mmol) ofN-(2-Methoxy-2-oxoethyl)-N-[3-(methylthio)-5-octadecyloxy)phenyl]glycinemethyl ester and 0.4 ml (2.4 mmol) of 6N NaOH in 15 ml of methanol wasstirred at reflux under argon for 2.5 hours. The solvent was removed atreduced pressure, the residue was acidified and the product wasextracted with ethyl acetate. The dried extract was concentrated to asolid which was triturated with hexane and filtered to give 0.287 g (94%yield), mp 129°-130°, ofN-(carboxymethyl)-N-[3-(methylthio)-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₂₉ H₄₉ NO₅ S: C, 66.50; H, 9.43; N, 2.67. Found: C,66.77; H, 9.63; N, 2.64.

EXAMPLE 167[[3-[bis(2-Methoxy-2-oxoethyl)amino]-5-(octadecyloxy)phenyl]sulfinyl]aceticacidmethyl ester

To a solution of 0.45 g (0.74 mmol) of[[3-bis(2-methoxy-2-oxoethyl)amino]-5-(octadecyloxy)phenyl]thio]aceticacid methyl ester in 30 ml of methylene chloride cooled in an ice bathwasadded 0.22 g (1.08 mmol) of 85% 3-chloroperoxybenzoic acid. Afterstirring in the ice bath for 3 hours, the solution was washed withNaHCO₃, dried and concentrated to a solid which was purified bychromatography on 40 g of silica gel using 50% ethyl acetate-hexane togive 0.4 g, mp 81°-83°, of[[3-[bis(2-methoxy-2-oxoethyl)amino]-5-(octadecyloxy)phenyl]sulfinyl]aceticacid methyl ester.

Anal. Calcd for C₃₃ H₅₅ NO₈ S: C, 63.33; H, 8.86; N, 2.24; S, 5.12.Found: C, 63.23; H, 8.99; N, 2.18; S, 5.15.

EXAMPLE 168[[3-[bis(Carboxymethyl)amino]-5-(octadecyloxy)phenyl]sulfinyl]aceticacid

A solution of 0.57 g (0.91 mmol) of[[3-[bis(2-methoxy-2-oxoethyl)amino]-5-(octadecyloxy)phenyl]sulfinyl]acetic acid methyl ester and 0.76 ml (4.55 mmol) of 6NNaOH in 100 ml of methanol was stirred at reflux under argon for 6hours. The solvent was removed at reduced pressure, the residue wasacidified andthe product was extracted with ethyl acetate. The driedextract was concentrated to a solid which was triturated with hexane andfiltered to give 0.42 g (80% yield), mp 138°-140°, of[[3-[bis(carboxymethyl)amino]-5-(octadecyloxy)phenyl]sulfinyl]aceticacid.

Anal. Calcd for C₃₀ H₄₉ NO₈ S: C, 61.72; H, 8.46; N, 2.40; S, 5.49.Found: C, 61.49; H, 8.52; N, 2.36; S, 5.44.

EXAMPLE 169 3-(Methylsulfinyl)-5-(octadecyloxy)benzoic acid

To 2.32 g (5.15 mmol) of 3-(methylthio)-5-(octadecyloxy)benzoic acidmethylester in 100 ml of methylene chloride cooled and stirred in an icebath wasadded 1.5 g (7.4 mmol) of 85% 3-chloroperoxybenzoic acid. Thereaction mixture was stirred in the ice bath for 1.5 hours, washed withNaHCO₃solution, dried and concentrated to a solid which was purified bychromatography on 40 g of 230-400 mesh silica gel using 50% ethylacetate-hexane to give 1.9 g (79% yield), mp 66°-68°, of3-(methylsulfinyl)-5-(octadecyloxy)benzoic acid methyl ester. The nmrand mass spectra were consistent with the structure.

To 1.88 g (4.03 mmol) of 3-(methylsulfinyl)-5-(octadecyloxy)benzoic acidmethyl ester in 75 ml of methanol was added 2.0 ml (12 mmol) of 6N NaOHand the solution was stirred at reflux under argon for 2.5 hours andthen was kept at room temperature for 14 hours. The solvent was removedat reduced pressure, the residue was acidified and the product wasextracted with ethyl acetate. The dried extract was concentrated atreduced pressureto a solid which was triturated with hexane and filteredto give 1.77 g, mp110°-112°, of3-(methylsulfinyl)-5-(octadecyloxy)benzoic acid.

Anal. Calcd for C₂₆ H₄₄ O₄ S: C, 68.98; H, 9.80; S, 7.08. Found: C,69.05; H, 9.51: S, 7.02.

EXAMPLE 170 3-(Methylsulfinyl)-5-(octadecyloxy)benzenamine

A mixture of 1.66 g (3.67 mmol) of3-(methylsulfinyl)-5-(octadecyloxy)benzoic acid, 3.4 ml of t-butanol(freshly distilled from sodium), 0.95 ml (4.4 mmol) ofdiphenylphosphoryl azide and 0.6 ml (4.4 mmol) of triethylamine in 20 mlof anhydrous toluenewas stirred at reflux under argon for 19 hours. Thereaction mixture was concentrated at reduced pressure and NaHCO₃solution was added to theresidue. The product was extracted withmethylene chloride and the dried extract was concentrated at reducedpressure to a solid which was purifiedby chromatography on 30 g ofsilica gel using 50% ethyl acetate-hexane to give 1.52 g (79% yield), mp91°-93°, of 3-(methylsulfinyl-5-(octadecyloxy)phenylcarbamic aciddimethylethyl ester.

A solution of 1.5 g (2.86 mmol) of3-(methylsulfinyl)-5-(octadecyloxy)phenylcarbamic acid dimethylethylesterand 1.1 ml (14.3 mmol) of trifluoroacetic acid in 50 ml ofmethylene chloride was kept at room temperature for 41 hours. Thesolvent was removed at reduced pressure, the residue was treated withNaHCO₃ solution and the product was extracted with methylene chloride.The dried extract was concentrated at reduced pressure to a solid whichwas recrystallized from methylene chloride-hexane to give 1.13 g (94%yield), mp 104°-106°, of 3-(methylsulfinyl)-5-(octadecyloxy)benzenamine.

Anal. Calcd for C₂₅ H₄₅ NO₂ S: C, 70.87; H, 10.71; N, 3.31; S, 7.57.Found: C, 71.00; H, 10.53; N, 3.27; S, 7.34.

EXAMPLE 171N-(2-Methoxy-2-oxoethyl)-N-[3-(methylsulfinyl)-5-(octadecyloxy)phenyl]glycinemethyl ester

A mixture of 1.12 g (2.64 mmol) of3-(methylsulfinyl)-5-(octadecyloxy)benzenamine, 0.75 ml (7.93 mmol) ofmethyl bromoacetate, 1.42 g (6.61 mmol) of 1,8-dimethylaminonaphthaleneand 0.11 g (0.74 mmol) of sodium iodide in 25 ml of anhydrousacetonitrileand 6 ml of anhydrous DMF was stired and heated under argonfor 96 hours. The solvents were removed at reduced pressure, 50 ml of0.5N HCl was addedto the residue and the product was extracted withethyl acetate. The dried extract was concentrated at reduced pressure toan oil which was purified by HPLC using 75% ethyl acetate-hexanefollowed by two recrystallizations from methylene chloride-hexane gave0.55 g (36% yield), mp 80°-82°, ofN-(2-methoxy-2-oxoethyl)-N-[3-(methylsulfinyl)-5-(octadecyloxy)phenyl]glycine methyl ester.

Anal. Calcd for C₃₁ H₅₃ NO₆ S: C, 65.57; H, 9.41; N, 2.47; S, 5.65.Found: C, 65.52; H, 9.18; N, 2.42; S, 5.92.

EXAMPLE 172N-(Carboxymethyl)-N-[3-(methylsulfinyl)-5-(octadecyloxy)phenyl]glycine

A solution of 0.53 g (0.93 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-(methylsulfinyl)-5-(octadecyloxy)phenyl]glycinemethyl ester and 0.8 ml (4.7 mmol) of 6N NaOH in 40 ml of methanol wasstirred at reflux under argon for 6 hours. The solvent was removed atreduced pressure, the residue was acidified and the product wasextracted with 10% THF-ethyl acetate. The dried extract was concentratedto a solid which was recrystallized from THF-ethyl acetate to give 0.42g (84% yield), mp 147°-149°, ofN-(carboxymethyl)-N-[3-(methylsulfinyl)-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₂₉ H₄₉ NO₆ S: C, 64.53; H, 9.15; N, 2.59; S, 5.95.Found: C, 64.40; H, 9.05; N, 2.42; S, 5.82.

EXAMPLE 173 3-(Di-decylaminocarbonyl)benzenamine

To an ice bath cooled solution of 0.80 g (2.69 mmol) of di-decylamineand 0.75 mL (5.4 mmol) of triethylamine in 10 mL of anhydrous methylenechloride was added dropwise a solution of 0.50 g (2.69 mmol) of3-nitrobenzoyl chloride in 5 mL of methylene chloride with stirring. Themixture was stirred at room temperature for 4 hours. Water was added,the organic layer was separated and dried. The solvent was removed atreduced pressure and the residual oil was purified by chromatography on30 g of silica gel using 12.5% ethyl acetate-hexane to give 1.0 g of3-(di-decylaminocarbonyl)-1-nitrobenzene as an oil. The nmr and massspectra were consistent with the structure. A mixture of 1.0 g of3-(di-decylaminocarbonyl)-1-nitrobenzene and 0.2 g of 10% palladium oncarbon in 20 mL of ethyl acetate and 20 mL of THF was stirred under ahydrogen atmosphere at room temperature for 2 hours when hydrogen uptakeceased. The catalyst was removed by filtration and the filtrate wasconcentrated to give 1.0 g of 3-(di-decylaminocarbonyl)benzenamine as anoil. The nmr and mass spectra were consistent with the structure.

EXAMPLE 174 N-(Carboxymethyl)-N-[3-di-decylaminocarbonyl)phenyl]glycine

A mixture of 1.0 g (2.4 mmol) of 3-(di-decylaminocarbonyl)benzenamine,3.8 mL (24 mmol) of benzylbromoacetate, 1.3 g (6 mmol) of1,8-bis(dimethylamino)naphthalene and 0.36 g (2.4 mmol) of sodium iodidein 20 mL of anhydrous acetonitrile and 5 mL of DMF was stirred underargonat reflux for 40 hours. The solvents were removed at reducedpressure, water was added and the product was extracted with ethylacetate. The dried extract was concentrated at reduced pressure and theresidue was purified by HPLC using 20% ethyl acetate-hexane to give 1.2g (70% yield) ofN-[3-(di-decylaminocarbonyl)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester as an oil. The nmr and mass spectra were consistentwith the structure. A mixture of 1.2 g ofN-[3-(di-decylaminocarbonyl)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester and 0.4 g of 10% palladium on carbon in 15 mL ofethylacetate and 15 mL of THF was stirred under a hydrogen atmosphere atroom temperature for 4.5 hours when hydrogen uptake ceased. The catalystwas removed by filtration and the filtrate was concentrated to an oilwhich was triturated with ether-hexane and filtered to give 0.6 g (67%yield, mp133°-136°) ofN-(carboxymethyl)-N-[3-di-decylaminocarbonyl)-phenyl]glycine.

Anal. Calcd for C₃₁ H₅₂ N₂ O₅ : C, 69.19; H, 10.07; N, 5.38. Found: C,69.38; H, 9.85: N, 5.27.

EXAMPLE 175N-[[3-(Octadecyloxy)-5-(tricyclo[3.3.1.1/3,7/]dec-1-ylcarbonyl)oxy]phenyl]glycine

A mixture of 0.36 g (0.67 mmol) of3-(octadecyloxy)-5-[(tricyclo[3.3.1.1/3,7/]dec-1-ylcarbonyl)oxy]benzenamine,0.31 mL (2.0 mmol) of benzylbromoacetate, 0.44 g (2.0 mmol) of1,8-bis(dimethylamino)naphthalene and 0.11 g (0.7 mmol) of sodium iodidein 10 mL of acetonitrile and 13 mL of DMF was stirred and refluxed underargon for 72 hours. The solvents were removed at reduced pressure, ethylacetate was added to the residue and the extract was washed with 0.01NHCl, with NaHCO₃ solution, dried and concentrated at reduced pressuretoan oil. Purification by chromatography on 75 g of silica gel using 15%ethyl acetate-hexane gave 0.177 g ofN-[[3-(octadecyloxy)-5-(tricyclo[3.3.1.1/3,7/]dec-1-ylcarbonyl)oxy]phenyl]glycinephenylmethyl ester as an oil. The nmr and mass spectra were consistentwith the structure. A mixture of 0.17 g ofN-[[3-(octadecyloxy)-5-(tricyclo[3.3.1.1/3,7/]dec-1-ylcarbonyl)oxy]phenyl]glycinephenylmethyl ester and 0.1 g of 10% palladium on carbon was shaken underan initial hydrogen pressure of 54 psi on a Parr Hydrogenator for 2.5hours. The catalyst was removed at reduced pressure and the filtrate wasconcentrated at reduced pressure to 0.12 g ofN-[[3-(octadecyloxy)-5-(tricyclo[3.3.1.1/3,7/]dec-1-ylcarbonyl)oxy]phenyl]glycineas a semisolid. The nmr and mass spectra were consistent with thestructure.

EXAMPLE 176N-[3-[3-[4-(1,1-Dimethylethyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester

A mixture of 1.0 g (1.92 mmol) ofN-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 0.55 g (2.0 mmol) of 4-(3-bromopropoxy)-1,1-dimethylethyl,0.53 g (3.8 mmol) of potassium carbonate and 0.29 g (1.92 mmol) ofsodium iodide in 30 mL of anhydrous acetone and 6 mL of anhydrous DMFwas stirredat reflux under argon for 65 hours. The solvents were removedat reduced pressure and the residue was extracted with methylenechloride. The extract was concentrated to a solid which wasrecrystallized from methylene chloride-methanol to give 0.85 g (62%yield, mp 56°-58°) of N-[3-[3-[4-(1,1-dimethylethyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester.

Anal. Calcd for C₄₃ H₆₉ NO₇ : C, 72.54; H, 9.77; N, 1.97. Found: C,72.78; H, 9.94; N, 2.04.

EXAMPLE 177N-(Carboxymethyl)-N-[3-[3-[4-(1,1-dimethylethyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine

A solution of 0.815 g (1.14 mmol) ofN-[3-[3-[4-(1,1-dimethylethyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester and 0.76 mL of 6N NaOH in 20 mL of methanol-10 mL ofdioxane was stirred at reflux under argon for 5 hours. The solvents wereremoved at reduced pressure, the residue was acidified with dilute HCland the product was extracted with ethyl acetate. The dried extract wasconcentrated at reduced pressure and the residue was crystallized frommethanol-water to give 0.72 g (92% yield, mp99°-101°) ofN-(carboxymethyl)-N-[3-[3-[4-(1,1-dimethylethyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine.

Anal. Calcd for C₄₁ H₆₅ NO₇ : C, 72.00; H, 9.57; N, 2.05. Found: C,72.25; H, 9.94; N, 2.04.

EXAMPLE 178 3-Amino octadecanoate (ester)

A solution of 1.3 mL (8 mmol) of octadecanoyl chloride in 5 mL ofmethylenechloride was added dropwise to a solution of 1.0 g (7.2 mmol)of 3-nitrophenol and 2.2 mL (16 mmol) of triethylamine in 30 mL ofmethylene chloride with stirring at room temperature. After stirring for2 hours, 100 mL of ether was added and the mixture was washed with 1NNaOH, dried and concentrated at reduced pressure to 1.5 g, mp 64°-65°,of 3-nitrophenol octadecanoate.

A mixture of 1.5 g of 3-nitrophenol octadecanoate (ester) and 0.3 g of10% palladium on carbon in 50 mL of ethyl acetate was shaken under aninitial hydrogen pressure of 52 psi on a Parr hydrogenator until uptakeceased after 4.5 hours. The usual workup and recrystallization frommethanol-water gave 0.7 g, mp 46°-47°, of 3-aminophenol octadecanoate(ester). The nmr spectrum was consistent with the structure.

Using this procedure heptadecyl isocyanate was treated with3-nitrophenol to give heptadecyl carbamic acid 3-nitrophenyl ester (mp66°-73°, Anal. Calcd for C₂₄ H₄₀ N₂ O₄ :C, 68.54; H, 9.59; N, 6.66.Found: C, 68.44; H, 9.88; N, 6.41) which was hydrogenated to giveheptadecylcarbamic acid 3-aminophenyl ester (mp 69°-75°, Anal. Calcd forC₂₄ H₄₂ N₂ O₄ :C, 73.80; H, 10.84; N, 7.17. Found: C, 73.79; H, 11.08;N, 6.84).

EXAMPLE 179 N-(3-Aminophenyl-N'-octadecylurea

A mixture of 0.5 g (3.6 mmol) of 3-nitroaniline, 1.2 mL (3.9 mmol) ofoctadecyl isocyanate 0.7 mL (5 mmol) of triethylamine and 0.1 mL of4-dimethylaminopyridine in 30 mL of anhydrous THF was stirred at refluxfor 18 hours. The reaction mixture was concentrated at reduced pressureand the residue was recrystallized from THF methanol-water to give 1.3 gof N-(3-nitrophenyl)-N'-octadecylurea.

A mixture of 1.3 g of N-(3-nitrophenyl)-N'-octadecylurea and 0.5 g of10% palladium on carbon in 60 mL of THF was shaken under an initialhydrogen pressure of 52 psi in a Parr hydrogenator unitl uptake ceasedafter 2 hours. The usual workup and recrystallization frommethanol-water gave 1.0g, mp 102°-104°, ofN-(3-aminophenyl)-N'-octadecylurea. Anal.Calcd for C₂₅ H₄₅ N₃ O: C,74.39; H, 11.24; N, 10.41. Found:C, 74.34; H, 11.11; N, 9.87).

EXAMPLE 180 3-(Octadecyloxy)-5-(2,2-diphenyl-1-oxoethoxy)benzoic acidphenylmethyl ester

Diphenylacetyl chloride [from the reaction of 2.0 g (4.7 mmol) ofdiphenylacetic acid with thionyl chloride] dissolved in 20 ml ofmethylenechloride was added dropwise to an ice cooled solution of 2.0 g(4.0 mmol) of 3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl esterand 1.1 ml (8.0 mmol) of triethylamine in 50 ml of methylene chloridewith stirring. The reaction mixture was stirred with ice bath coolingfor 1 hour and thenat room temperature for 20 hours and then was washedwith 1N HCl and with NaHCO₃ solution. After drying the solvent wasremoved at reduced pressure and the crude product was purified bychromatography on 50 g of silica gel using 10% ethyl acetate-hexane togive 2.5 g, mp 47°-49°, of3-(octadecyloxy)-5-(2,2-diphenyl-1-oxoethoxy)benzoic acid phenylmethylester. The nmr and mass spectra were consistent with the structure.

EXAMPLE 181 3-(Octadecyloxy)-5-[(tricyclo[3.3.1.1/3,7/]dec-1-ylcarbonyl)oxy]benzoic acid phenylmethyl ester

1-Adamantane carboxylic acid chloride (0.067 g) in 1 mL of methylenechloride was added to a stirred solution of 0.153 g of3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester and 0.09 mL oftriethylamine in 10 mL of methylene chloride. The reaction mixture wasstirred at room temperature for 17 hours and was then washed with 1N HCland with NaHCO₃ solution. After drying the solvent was removed atreduced pressure and the crude product was purified by chromatography on20 g d silica gel using 10% ethyl acetate-hexane to give 0.163 g of3-(octadecyloxy)-5-[(tricyclo[3.3.1.1/3,7/]dec-1-ylcarbonyl)oxy]benzoicacid phenylmethyl ester as an oil. The nmr spectrum served to confirmthe structure.

EXAMPLE 182N-[3-Hydroxy-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester andN-(2-Methoxy-2-oxoethyl)-N-[3,5-bis[(12-phenoxydodecyl)oxy]phenyl]glycinemethyl ester

A mixture of 1.0 g (3.7 mmol) ofN-[(3,5-dihydroxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester,1.27 g (3.7 mmol) of 12-phenoxydodecyl bromide and 0.51 g (3.7 mmol) ofpotassium carbonate in 20 ml of DMF was stirred and heated at 80° for 24hours under argon. The usual workup followed by purification bychromatography on 40 g of silica gel. Elution with 25% ethylacetate-hexane gave 0.57 g, mp 61°-63°, ofN-(2-methoxy-2-oxoethyl)-N-[3,5-bis[(12-phenoxydodecyl)oxy]phenyl]glycinemethyl ester. Elution with 50% ethyl acetate-hexane gave 0.53 g, mp65°-67°, ofN-[3-hydroxy-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester.

Anal. Calcd for C₃₀ H₄₃ NO₇ : C, 68.03; H, 8.18; N, 2.64. Found: C,67.93; H, 8.07; N, 2.57.

EXAMPLE 183N-[3,5-bis[(12-Phenoxydodecyl)oxy]phenyl]-N-(carboxymethyl)glycine

A solution of 3.5 g (4.43 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3,5-bis[(12-phenoxydodecyl)oxy]phenyl]glycinemethyl ester and 3 ml (18 mmol) of 6N NaOH in 150 ml of methanol and 50mlof dioxane was stirred at reflux under argon for 19 hours. The usualworkupfollowed by recrystallization from acetone-hexane gave 3.2 g, mp72°-74°, ofN-[3,5-bis[(12-phenoxydodecyl)oxy]phenyl]-N-(carboxymethyl)glycine.

Anal. Calcd for C₄₆ H₆₇ NO₈ : C, 72.50; H, 8.86; N, 1.84. Found: C,72.37; H, 9.02; N, 1.86.

EXAMPLE 184N-[3-[2-[2-(2-Ethoxyethoxy)ethoxy]ethoxy]-5-[(12-phenoxydodecyl]oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester

A mixture of 1.2 g (2.27 mmol) ofN-[3-hydroxy-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 2.73 g (11.37 mmol) of2-[2-(2-ethoxyethoxy)ethoxy]ethylbromide, 0.94 g (6.8 mmol) of potassiumcarbonate and 1.0 g (6.8 mmol) of sodium iodide in 40 ml of acetone and20 ml of DMF was stirred at reflux under argon for 64 hours. After theusual workup the product was purified by HPLC using 40% ethylacetate-hexane to give 1.16 g (74% yield), mp<24°, ofN-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester.

EXAMPLE 185N-(Carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-[(12-phenoxydodecyl)-oxy]phenyl]glycine

A solution of 1.15 g (1.67 mmol) ofN-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester and 1.4 ml (8.4 mmol) of 6N NaOH in 50 ml of methanol and10 ml of dioxane was stirred at reflux underargon for 19 hours. Afterthe usual workup the product was crystallized from acetone-hexane togive 0.94 g (85% yield), mp 58°-61°, ofN-(carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)-ethoxy]ethoxy]-5-[(12-phenoxydodecyl)oxy]phenyl]glycine.

Anal. Calcd for C₃₆ H₅₅ NO₁₀ : C, 65.33; H, 8.38; N, 2.12. Found: C,65.24; H, 8.49; N, 1.99.

EXAMPLE 186N-(2-Methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-[(12-phenoxy-dodecyl)oxy]phenyl]glycinemethyl ester

A mixture of 1.5 g (2.83 mmol) ofN-[3-hydroxy-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 1.2 g (4.25 mmol) of3-[(4-methylsulfinyl)phenoxy]propylbromide, 0.78 g (5.66 mmol) ofpotassium carbonate and 0.64 g (4.25 mmol) of sodium iodide in 40 ml ofacetone and 10 ml of DMF was stirred at reflux under argon for 6 days.The usual workup followed by purification by chromatography on 45 g of230-400 mesh silica gel using 10% ethyl acetate-hexane gave 1.1 g (54%yield), mp 47°-49°, ofN-(2-methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-[(12-phenoxy-dodecyl)oxy]phenyl]glycine methyl ester.

EXAMPLE 187N-(Carboxymethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-[(12-phenoxydodecyl)oxy]phenyl]glycine

A solution of 1.1 g (1.52 mmol) ofN-(2-methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-{(12-phenoxy-dodecyl)oxy]phenyl]glycinemethyl ester and 1.3 ml (7.8 mmol) of 6N NaOH in 100 ml of methanol wasstirred at reflux under argon for 4 hours. After the usual workup theproduct was recrystallized from acetone-hexane to give 0.93 g (88%yield), mp 106°-108°, ofN-(carboxymethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-[(12-phenoxydodecyl)oxy]phenyl]glycine.

Anal. Calcd for C₃₈ H₅₁ NO₉ S: C, 65.40; H, 7.37; N, 2.01; S, 4.59.Found: C, 65.25; H, 7.38; N, 2.13; S, 4.58.

EXAMPLE 188N-[3-[6-(2,3-Bisphenylmethoxy)phenyl]hexyloxy]-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester

A mixture of 1.7 g (3.2 mmol) ofN-[3-hydroxy-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester, 1.5 g (3.37 mmol) of1-(6-bromohexyl)-2,3-bis(phenylmethoxy)benzene, 1.3 g (9.6 mmol) ofpotassium carbonate and 0.96 g (6.4 mmol) of sodium iodide in 60 ml ofacetone and 20 ml of DMF was stirred at reflux under argon for 7 days.Theusual workup followed by purification by HPLC using 25% ethylacetate-hexane gave 2.15 g (74% yield) ofN-[3-[6-(2,3-bisphenylmethoxy)phenyl]hexyloxy]-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester as an oil. The nmr and mass spectra were consistent withthe structure.

EXAMPLE 189N-(Carboxymethyl)-N-3-[6-[(2,3-bisphenylmethoxy)phenyl]hexyloxy]-5-[(12-phenoxydodecyl)oxy]phenyl]glycine

A solution of 2.13 g (2.36 mmol) ofN-[3-[6-(2,3-bisphenylmethoxy)phenyl]hexyloxy]-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycinemethyl ester and 2.0 ml (12 mmol) of6N NaOH in 125 ml of methanol and 25ml of dioxane was stirred at reflux under argon for 6 hours. After theusual workup, the product was purified by crystallization fromacetone-hexane to give 1.78 g (86% yield, mp 81°-84°) ofN-(carboxymethyl)-N-3-[6-[(2,3-bisphenylmethoxy)phenyl]hexyloxy]-5-[(12-phenoxydodecyl)oxy]phenyl]glycine.

Anal. Calcd for C₅₄ H₆₇ NO₉ : C, 74.20; H, 7.73; N, 1.60. Found: C,74.48; H, 7.84; N, 1.81.

EXAMPLE 190N-(Carboxymethyl)-N-[3-[6-(2,3-dihydroxyphenyl)hexyloxy]-5-[(12-phenoxydodecyl)oxy]phenyl]glycine

A mixture of 1.74 g ofN-(carboxymethyl)-N-3-[6-[(2,3-bisphenylmethoxy)phenyl]hexyloxy]-5-[(12-phenoxydodecyl)oxy]phenyl]glycineand 0.6 g of 10% palladium on carbon in 100ml of THF was stirred under ahydrogen atmosphere until uptake ceased after3 hours. After the usualworkup, the product was purified by trituration with hexane to give 1.26g (91% yield, mp 129°-131°) ofN-(carboxymethyl)-N-[3-[6-(2,3-dihydroxyphenyl)hexyloxy]-5-[(12-phenoxydodecyl)oxy]phenyl]glycine.

Anal. Calcd for C₄₀ H₅₅ NO₉ : C, 69.24; H, 7.99; N, 2.02. Found: C,69.24; H, 7.85; N, 1.93.

EXAMPLE 191 TABLET FORMULATION (Wet Granulation)

    ______________________________________                                                           mg/tablet                                                  Item Ingredient          25 mg   100 mg                                                                              500 mg                                 ______________________________________                                        1.   N-[(carboxymethyl)-N-[3-[2-[2-                                                                    25      100   500                                         (2-ethoxyethoxy)ethoxy]ethoxy]-                                               5-(octadecyloxy)phenyl glycine                                           2.   Lactose Anhydrous   143     132   --                                     3.   Pregelatinized Starch                                                                             10      16    30                                     4.   Modified Starch     20      30    40                                     5.   Magnesium Stearate   2       2     6                                          Total               200     280   576                                    ______________________________________                                    

Manufacturing Procedure:

1. Mix Items 1, 2 3 and 4 and granulate with water.

2. Dry the granulation at 50° C.

3. Pass the granulation through suitable milling equipment.

4. Add Item 5 and mix for three minutes; compress on a suitable press.

EXAMPLE 192 CAPSULE FORMULATION

    ______________________________________                                        Item Ingredient          mg/capsule                                           ______________________________________                                        1.   N-[(carboxymethyl)-N-[2-[2-                                                                       25     50   100  500                                      (2-ethoxyethoxy)ethoxy]ethoxy]-                                               5-(octadecyloxy)phenyl glycine                                           2.   Lactose Hydrous     143    168  148  --                                  3.   Corn Starch         20     20   40   70                                  4.   Talc                10     10   10   25                                  5.   Magnesium Stearate   2      2    2    5                                       Total               200    250  300  600                                 ______________________________________                                    

Manufacturing Procedure:

1. Mix Items 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add Items 4 and 5 and mix for 3 minutes.

3. Fill into suitable capsules.

We claim:
 1. A compound of the formula: ##STR57## wherein R₂ ' is loweralkyl or benzyl;R₃ is CH₃ (CH₂)_(n) O--, where n is 9 to 17; R₄ is CH₃(CH₂)_(n) O--, where n is 9 to 17; and m is 1 to
 3. 2. A compound ofclaim 1, wherein R₂ ' is lower alkyl.
 3. A compound of claim 1, whereinR₂ ' is benzyl. 4.N-[3,5-bis(Decyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycinephenylmethyl ester.